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Friday, May 15, 2009


U. Santhi KrishnaHH, D. Jyothis, Sijo Pattam
National College of Pharmacy, Manassery, Calicut

Cite this: U. Santhi Krishna, D. Jyothis, Sijo Pattam, "SAFETY OF INHALED CORTICOSTEROIDS IN COPD", B. Pharm Projects and Review Articles, Vol. 1, pp. 1498-1536, 2006. (


    Chronic obstructive lung disease is defined as a disease state characterised by the presence of airflow obstruction owing to chronic bronchitis or emphysema. The term Chronic obstructive airway disease and chronic obstructive pulmonary disease are synonymous with COLD. Chronic bronchitis is a condition with chronic or recurrent excess mucus secretion in to the bronchial tree with cough that occurs on most day during a period of at least 3 months of the year for at least 2 consecutive years in a patient in whom other chronic causes of cough have excluded. Emphysema has been defined as a condition of the lung characterised by abnormal, permanent enlargements of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls , yet without obvious fibrosis.

    Of the numerous risk factors associated with the development of chronic bronchitis and emphysema clearly cigarette smoking is the most common. The median risk ratio for smokers versus non- smokers to develop chronic bronchitis is 5.3 for men and 1.2 for woman. Children and spouses of smokers are also at increased risk of developing significant pulmonary dysfunction by passive smoking , also known as environmental tobacco smoke or second smoke.

    Increasing age, male gender, and existing impaired lung function also have been identified as risk factor for developing COPD. Reduced lung function and deaths from COPD are higher for individuals working at gold or coal mining, in the glass is ceramic industries with expose to silico dust, and in jobs that expose them to cotton dust, tolueen di lsocyanate, or asbestoses.





    a1 – Antitrypsin (AAT) deficiency clearly has been defined as a genetic disorders that contribute to the risk of developing COLD specifically emphysema. True AAT deficiency accounts for less than 1% of COLD cases.

    In COPD, these are chronic inflammatory processes that are distinctly different from those seen in asthma. Patients with COPD have increased number of macrophages, CD8+(cyto toxic) T cell,and nutrophills. There is probably a complex interaction b/w these inflammatory mediators and cells that result in progressive changes in small airways and parenchyma that contribute to obstruction. At the site of destruction, there are large no. of macrophages that can be activated by Cigarette smoke and other irritation to release neutrophils chemoctactic factor (IL-β4 & IL – 8). When neutrophils and macrophages are activated, they release proteins that breakdown connective tissue in the lung parenchyma, leading to emphysema and mucous production. Cyto toxic T cells may further contribute to the distruction of alveolar walls through the release of porphyrin or tumor necrosis factor -a (TNF - a)


What is COPD


    COPD is defined as a disease state characterised by air flow limitation that is not fully reversible. The air flow limitation is usually both progressive or associated with an abnormal inflammatory response of the lungs to noxius particles or gases.


    In 1996, approximately over 16 million men and women suffering from COPD in US and more than 52 million people world wide. Prevalence of COPD in individuals under45 years old is low while the prevalence to highest in patients over 65 years old. The prevalence in those over 65 was four fold that in the 45-64 year old group.

Risk factors for the development of COPD

    Major                                 Minor
Smoking                             Air Pollution
Age                                 Race
Male gender                             Nutritional status
Existing impaired lung function                 Family history
Occupation                             Socioeconomic status
a1 – Anti Trypsin deficiency                     Respiratory tract infects
                                Bronchial Creativity


COPD mainly include two disease states. 1) chronic bronchitis 2) emphysema.


Chronic bronchitis
    Chronic bronchitis is characterized by excessive tracheobronchial mucus secretion with cough. This excessive production of mucus results from hyperplasia and hypertrophy of mucus producing glands and goblet cells owing to continued bronchial irritation. Additional morphologic changes occur in the bronchi, including increased smooth muscle, cartilage atrophy, inflammation characterized by neutrophil and lymphocyte infiltration, and loss of cilia. These bronchial changes do not contribute significantly to obstruction.

    In the COLD patient with predominant chronic bronchitis, changes in the peripheral airways contribute most to obstruction. Inflammation exists with mucus production and narrowing of the lumen in the more distal noncartilageous or membranous bronchioles. In addition, there is fibrosis, tortuosity and irregularity of these smaller airways.


    The lung damage produced by smoking or exposure to other chronic irritants has long been considered to begin in the small air ways. As chronic bronchitis progresses over several years, the changes in small airways begin to impair ventilation whereas perfusion remains fairly adequate resulting in a imbalance and hypoxemia. Hypoxemia leads to pulmonary hypertension with subsequent right ventricular failure. The persistent hypoxemia stimulates erythropoiesis with resulting secondary polychthemia and increased blood viscosity, with its attendant complications of mental confusion and thrombotic stroke. An additional component of chronic bronchitis is repeated respiratory infections.


    Emphysema is a condition in which there is destruction of walls within the acinus such that the surface area for gas exchange is diminished. Proximal acinar emphysema: This type of emphysema is confined largely to the proximal portion of the acinus, with the respiratory bronchioles being particularly affected. Panacinar emphysema: These patients have a deficiency of protease inhibitors such that proteases are allowed to destroy the alveolar walls of the acinus. This type usually involves the entire lung field. In centrilobular emphysema specifically caused by smoking an imbalance develops between the protective protein inhibitors and proteases from activated neutrophils and macrophages. Cigarette smoke is also though to impair the synthesis of elastin alveolar inflammatory cells in smokers with emphysema have been shown to spontaneously inactivate proteinase inhiotor, suggesting that the progressive lung damage is related to an ongoing inflammation in peripheral airways.



COPD is characterised by chronic obstruction of expirating flow affecting peripheral airways, associated with chronic bronchitis (muscle hypersecretion with globlet cell and submucosal gland hyperplasia) and emphysema (Destruction of airway parenchyma) together with fibrosis tissue damage and inflammation of small airways cytokines are extra cellular signaling proteins. Increased levels of interleukin (IL-6),(IL- 1) beta which further increasing during exacerbation, and the bronchiolar epithelium over express monocyte chemotatic protein (MCP)-1 & IL-8.

    In COPD TGF beta is released from the epithelium and act on smooth muscle, leading not only to collagen deposition but also to interference with the reception density of beta exceptions on airway smooth muscle and loss bronchodilation response, TNF - a & IL – 1 stimulate macrophages to produce matrix metallo protinase and bronchial epithelial cells to produce extra cellular matrix glycoprotein such as tenascin. TGF – β or EGF activate proliferation of fibroblastic. The role of these is a potential for anticytokine therapy I COPD.


    The mechanisms that cause airways limitation in COPD are different from asthma. three mechanism contribute to air flow limitation,

  • Disruption of alveolar attachments of small airways
  • Narrowing of airway wall itself
  • Mucous hypersecretion.


    The diagnosis of COPD is suggested by findings on history and / or physical examination or is confirmed by laboratory test, usually with a supportive risk factor (eg at familial COPD & or of Cigarette exposure). Spirometry is indispensable in establishing the diagnosis. Spirometry shows a used FEV1 & FEV1 / forced vital capacity ratio. Evidence reversible of airflow obstructed defined as a post bronchodilator risk of FEV1 and or FVC by 12% and 200ml, is present in upto 2/3 of patience within serial testing. Measurement of diffusing capacity for CO may help to differentiate b/w emphysema or chronic bronchitis specially capacity indicates a loss of alveolar capillary which suggest emphysema.

    The common signs and symptoms include cough, dyopnea on exccrtion, and increased phlegm production. Additional signs and symptoms include wheezing, prolongs expiration with paused lip breathing, barrel chest, use of accessory muscles of breathing
    and in advanced cases cyanosis, evidence of light heat failure and peripheral edema. A chest radiograph usually show hyper inflation & flattening of the diaphragms. Although not indicated for routine clinical care, high resolution computed tomography (CT) imaging can image the bullai or blebs that are the consequence of alveolar breakdown.



Treatment aims for patients with COPD

  • Lessen airflow limitation
  • Prevent and treat secondary medical complication such as hypoxemia and infections.
  • Decrease respiratory symptoms and improve quality of life.

I)     Antibiotics
    Prophylactic antibiotic have no place in the management of COPD. Antibiotic therapy is however vital it a patient develop present sputum.

    The normal pathogen involved is streptococcus pneumonia. H. Influenza. The usual antibiotic of choice is amoxicillin, erythromycin, doxycycline. If the infection follows influenza, s. aurous may be present, and an antistaphylococcal agent such as flucloxacillin should be added to the regimen.

II)     Bronchodilators:
    Bronchodilators in COPD are used to reverse airflow limitation. As the degree limitation varies widely their effectiveness should be assessed in patient using respiratory function tests and by assessing any subjective improvement in exercise tolerance or relief symptoms such as where and cough.

Inhaled β2 adrenoreceptor agonists

    Selective β2 agonist should be tried initially since they provide rapid relief and have a low incidence of side effects. Inhaled treatment is as efficacious as oral agent and is therefore prefered having few side effects. In COPD higher doses is required this may result in increased incidence of side effects.

Anti cholinergic drugs

    In COPD patients, parasympathetic (Vagal) airway muscle tone is the major reversible component. In haled anticholinergic drug reverse this vagal tone is have a significant bronchodilation effects, especially in the elderly. The drug of choice are the quarternary atropine derivative itratropium bromide and oxitropium, which when inhaled give local effects, with little systematic absorption. The inhaled anticholinergic have a slower onset of action than β2 agonist combination therapy with β2 agonist may produce additive bronchodilation.


    Theophyllins are weak bronchodilator and are said to have additional bronchodilator effect in COPD. Care should be taken while prescribing theophylline. The clearance of theophylline is effected by many factors including, cigarette smoking, viral pneumonia, heart failure is concurrent drug treatment.


    A therapeutic trial of corticosteroids should be tried in patients with COPD whose condition is clinically stable and who are already on maximum bronchodilation therapy. It is difficult to predict which patients will benefit from steroid therapy. Patients should be given steroids for 2 weeks. Lung function test should be performed together both patients record of peak flow measurements, exercise tolerance and a diary of symptom frequency or severity maintenance steroid should be prescribed subsequently in both subjective and objective measurements are improved for eg: a 20-25% increase in lung function test. If a patient unfit from the trial of steroids, inhaled steroids should ideally used as maintenance treatment although. Only about 50% patients who respond to oral steroids to inhaled steroids.

    At inhaled doses side effects of this therapy on the rate of decline of drug function has been questioned further study is required to define the place of inhaled coticosteroids in COPD. Ideally only if maximal inhaled doses fail to Ct1 symptoms should oral steroids be used. These must be used in the smaller dose possible to minimize long term adverse effects & should be used in Conjuntion with inhaled steroids.







Pulmonary rehabilitation:

    Patients should participate in a co – ordinate programme of non pharmacological treatment with support from all members of the health care team. They should includes advice and support on stopping smoking, nutritional assessment; aerobic exercise containing to increase capacity of endurance for exercise. Pulmonary rehabilitation programmers that include at least 4 weeks exercise training have been shown to improve dyspnoea and patients COPD Ct1. These benefit were greater than those seen with bronchodilators

Stoping smoking:

    To give up smoking, which has been described as a form of drug addiction. Requires self – motivation. The reported success rates of different anti – smoking methods have varied from 10 – 30%. members of the health care team educate smokers about dangers and actively encourage and motivate those who want to give up.

    For those patients with obstructive airway disease with a degree of reversibility, correct use of inhaled therapy is a vital part of overall management. If inhaled steroids are prescribed, the importance of regular administration must be prescribed. The incorrect use of any inhaled will lead to sub –therapeutic dosing. The correct use of inhaled is therefore as vital is the management of obstructive airway disease patients as it is for patience with asthma.


    Studies have shown that only about 50% of patience on long term oxygen therapy. Emphasis must be given to the improvement of quality of life gained from treatment rather idea of during condinually fed to Oxygen therapy.


Why steroids are used in COPD?

Inhaled corticosteroids are now widely used in the treatment of chronic obstructive pulmonary disease

COPD as an Inflammatory Disease
The anti inflammatory mechanism by which steroids produce there beneficial effect in copd include
  • Reduction in capillary permeability to dicrease mucus
  • Inhibition of release of proteolytic enzymes from leukocytes
  • Inhibition of prostaglandin
    There is an increasing    evidence that COPD is associated with chronic inflammation in the airways, and parenchyma. This has been used as a rational for the use of inhaled corticosteroids in COPD, by analogue the striking suppressive effects of inhaled corticosteroids on airway inflammation and symptoms in asthma but the inflammatory pattern in COPD differs markedly from that seen in asthma with prepondence of macrophages or CD8+ T – lymphocytes in the airway and lung parenchyma and an increase in macrophages and neotrophils in sputum and bronchoalveolar lavage, in contrast to the increase in cosinophils and activation of mast and CD4+ T- cells that are characteristic of asthma. In both chronic disease there is an increased production of cytokines but the pattern differs in COPD, compared to IL – 4, IL – 5 & IL -13 in asthma. Corticosteroids are very effective in suppressing airway inflammation in asthma and have potent inhibitory effects on cosinophilc inflammation, with reduced production, recruitment, activation and particularly survival of eosinophilia by construct double blind placebo controlled studies in carefully characterised patients have shown that even high doses of inhaled corticosteroids do not reduce inflammatory cell numbers, concentration of cytokines or proteases. Another study found a small inhibitory effect of inhaled corticosteroids on neotrophils count in induced sputum of patients with COPD, but these study was not controlled and there was a high eosinophillia count suggesting that asthmatic patients has been included. The lack of effects of corticosteroids on inflammatory markers in induced sputum has been confirmed in a preliminary study that showed no effect on bronchial biopsies. It appears that COPD is a steroid resistant disease.



    Numerous trials have been performed that have evaluated the use of inhaled corticosteroids in the population. The effect of steroid based on trial is difficult because treatment duration and doses of steroids used differ between trials as do and points of effects and interpretation of these end points. Evaluating the two of the most recent larger and well designed studies
  • European Respiratory Society on COPD(EUROSCOP)
  • Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE)


This study examines the distribution of the spirometric response to Prednisolone in a well defined population of patience with non asthmatic COPD, and its relationship with subsequent changes in FEV1, health status, and exacerbation rate over the following 3 years


    Patients eligible for participation in the inhaled steroids in obstructive lung disease (ISOLDE) study had a clinical diagnosis of non asthmatic COPD, were aged 40 – 75 yrs and had a history of current or previous smoking. At baseline, post dilation FEV1 was > 0.81 and < 80% predicted. Patience with a clinical diagnosis of asthma, there requiring any non trial anti –inflammatory treatment for long disease or β adrenergic blockers, patients with a life expectancy <5 years, and those unable to meet the required standard for spirometry at the pose – trial visit were excluded. Nasal and ocular topical corticosteroids were allowed, as were methylxanhines and long acting bronchodilator. All patients were given salbutamol 200mg and ipratripium bromide 80mg to use as required throughout the trial.


    Patients entered a run in period of 8 weeks, when no oral or inhaled corticoids were taken. Those included in the ISOLDE trial were then rendomised in a double blind manner to treatment with fluticasone propionate 500mg twice daily or matched placibo or 3 years,but were given Prednisolone 0.6mg /kg for 14 days before starting the randomized treatments. Spirometric testing was performed at entrollment (Visit O), after 4 weeks(Visit 1) after 8 weeks (Visit 2) and again after the 2 weeks Prednisolone trial (Visit3).

The protocol was approved by cthics committee of each participating centre, and all subjects gave written informed consent.


    Smoking history was validated using exhaled breath CO and urinary cotinine measurements. Smokers were defined as those currently level of > 40ng/ml. ex: smokers were those who had given up smoking and had a urinary cotinine level of < 40ng/ml.

    Gas transfer was measured using the single breath. Skin prick tests with diluent control, 10% histamine, and allergen extracts of dermatophagoides pteronysinus, cat etander, mixed grass pollens, and aspergillus fumigatus were read at 5 times maximum wheal diameters were measured and atony was defined as a > 3mm wheal to atleast oneallergen extract with appropriate controls. Health status was measured using the st Geoge's Respiratory Questionnaire(SGRQ).








    Measurements were made at the same time of day for each subject after withholding short acting bronchodilators for 4hrs., oral as long acting bronchodilators for 12 hrs. Caffiene containing products for 4hrs, smoking for 2hrs, and large meal for 1hrs. measurements were mode seated after 15 minutes resting. The spirometric tests were performed ex – bronchodilators and 30 minutes after taking 80mg. ipratiropicno bromide and 200mg salbutamol.

    An exacerbation was defined as a chest problem requiring treatment with oral corticosteroids and / or antibiotics as defined by the treating physician. Two 14 day exacerbations were permitted in any 3 month periods. Patients were withdrawn if exacerbations exceeded this. At each clinic visit the number of exacerbations in the previous 3 months was recorded. Exacerbations were calculated as the rate per day in the trial per year.


Baseline Characteristics
Patients completing oral steroid
trial and providing valid data
Mean (SD) age  
Male, N(%) 
407 (78%) 
Atopic, N(%)(missing) 
Current smoker, N(%) 
Ex – smoker, N(%) 
Mean (SD) Smoking (Pack years) 
Mean (SD) FEV1, (Missing pre-bronchodilator)
Mean (SD) FEV1 Pre – bronchodilator
(% predicted) 
Mean (SD) FEV1, post – bronchodilator  
Mean (SD) FEV1 post – bronchodilator
(% predicted )
Mean (SD) DFEV1 post – pre bronchodilator (ml)
Mean (SD) FVC Post – bronchodilator 
Mean (SD) FVC post – bronchodilator
(% predicted) 
Mean (SD) tico (% predicted)

Missing = 76 
FEV1 = Forced exploratory volume in 1 second
FVC = forced vital capacity
Tico = Carbon monoxide transfer factor 







    To investigate the factors associated with the 2 weeks prednisodone trial response, the change in post – bronchodilator FEV1, befor and after Prednisolone Q was used as the dependent variable in multivariate analysis using the generalized linear model procedure in SAS. Independent variables were baseline smoking status (current or ex – smokers) age, post – bronchodilator FEV1, FEV1 reversibility after sulbutamol and ipratropium bromide, Sex, and atopy (yes or no).

    Collaban and collegues defined steroid respondense as patients with response to Prednisolone of > 20% of baseline. The American thoracic society (ATS) defines responders as those with a response of > 12% baseline and > 200ml. these were termed the collaban and ATS criteric, respectively, and were used to determine difference between steroid responders and non –responders.

    The relationship between the Prednisolone response and the change in FEV1 and health status in the 3 year comparison of Fluticasone propionate and placebo wearer investigated by including the FEV1, post – bronchodilator response to Prednisolone as a covariate in the mixed effects models. The number of exacerbation occurring during the treatment period was analysed using a maximum like hood based analysis, assuming the poioson distribution, with time on treatment as an offset variable, using the SAS GENMOD procedure for fitting generalized linear models. The model included terms of age, sex, centre, smoking status, treatments. Classification, and the treatment x responders classication interaction.


    The results are confirmed to the 524 subjects who had taken atleast 80% of the Prednisolone treatment and had FEV1 readings unaffected by respiratory exacerbations baseline characteristic of this are obown in Table1. A further 47 patients stated that they had taken less than 80% of the prescribed Prednisolone close and 77 were excluded because of exacerbation within 4 weeks of the pre or post – Prednisolone visits, these 124 patients were not included in the analysis response to 14 day course of Oral steroid.

    The mean pre – bronchodilator FEV1 response to Prednisolone was 69ml (95%) Cl 53 to 85) and the mean post – bronchodilator response wsa 60ml(95% Cl 45-74). The post – bronchodilator response was distributed across a narcrohl;es range of values than the pre – bronchodilator response.

Separation of corticosteroid "responders" from non – "responders"

    The post – bronchodilator FEV1 response to Prednisolone (fig1) was unimodaling distributed, which suggests that the definition of responders and and non- responders is arbitrary. According to the callaban definition, 62 patients were responders with a mean (SD) change of 329(145) ml and 462 were non – responders with a mean (SD) change of 25(127)ml. according to the AIS definition, 74 responders had a mean (SD) chande of 324(130)ml and 450 non – responders were not significantly different at beseline in terms of age, atopy, sex and pack years of smoking

Relation ship between variability I FEV1 & Prednisolone response
Change in FEV1 
- 20% to +20% 
Visit 1 Visit 0 
Visit 2 – Visit 1  
47ml (105ml) 
-127ml( 187ml) 

Table 2 shows the change I post – bronchodilator FEV1, between measurements taken during the run – in phase by Prednisolone response category. In the 4 weeks immediately preceding the Prednisolone trial, the mean (SD) FEV1, fell significantly more in the responders gp (-127 (187)ml) than in the intermediate gp(-10(132)ml) and the group who deteriorated after Prednisolone (+47(105)ml) patients with a post – bronchodilator FEV1 response to Prednisolone of >20% of baseline had a significantly greater than fall in FEV1 during the run – in phase than those with a lower or negative response to Prednisolone (PL0.01_. there was no significant difference in prednisolone response between steroid native patients (48ml, n = 236) and those withdrawn from inhaled steroids at least 8 weeks previously (71ml, n=238, p = 0.1).

Characteristic of smokers and confirmed ex – smoker who received Prednisolone. 
Ex – smokers
(n= 278) 
(n = 246) 
P value 
Male (%) 
Alopic (%) 
FEV1 pre – bronchodilator(l) 
FEV1 pre – bronchodilator(% predicted) 
FEV1 post – bronchodilator (l) 
FEV1 post – bronchodilator ( % predicted ) 
D FEV1 post – bronchodilator
FVC pre – bronchodilator (l) 
FVC pre – bronchodilator(% predicted) 
FVC post – bronchodilator (l) 
FVC post – bronchodilator (% predicted)  
Change in FEV1(ml) following Prednisolone (mean (SE) from multivariate model) 
Values are mean (SD) unless otherwise indicated.
FEV1 = Forced expiratory volume in 1 second
FVC = Forced vital capacity. 

A multivariate analysis showed that age, atopy, sex, base line FEV1, and bronchodilator response were not significantly related to the response to Prednisolone (P>0.05) . however the FEV1 response to Prednisolone was greater in ex – smokers (mean (SE)) 35(II) ml, P < 0.01) (the characteristic of the population of smokers and ex – smokers are shown in Table3).

Smokers were 4 years youngers than the ex- smokers and difference in FEV1 indicated that they also had better lung function. (the model also gave the following estimates for the presnisolone responses atopics 48ml, non – atopic 65ml; mean 54ml, woman 55ml)


These was no significant relationship between the response to Prednisolone and subsequent decline in FEV1 regardless of response definition or treatment subgroup. A typical patient with a 14 day response to Prednisolone of 50ml would be predicted to obtain an additional immediate benefit of 8 ml on Fluticasone but no difference in the subsequent FEV1, decline compared with a patient with no response to Prednisolone. However, as this benefit is so small, even if it assumed that the interaction is real, it is of no clinical relevance. it did not predict the rode of deterioaths in health status as measured by the SGRQ total score (P=0.1)


A poisson analysis was performed to relate the number of exacerbation to treatment, Prednisolone response using the AIS or collaban definition, Fluticasone reduced the no. of exacerbation by an average of 20%, but there was no evidence that the Prednisolone response as defined the ATS was an indicator of effect of Fluticasone using the callaban difenition, the effect of Fluticans on the exsponders was a 55% reduction in the number of exacerbation, while the effect on the non – responders was 15%






This is the largest gr of patients with COPD studied in a formal corticosteroid trial and, in particular with carefully controlled and audited spermatic tests performed at the same time of day . the patience were similar to those in whom a trial of steroids is generally recommended, being at the stage of their disease were medical attention had been sought. The changes in post bronchodilator FEV1, after Prednisolone were unimodally distributed about the mean with no evidence of a separable responder group. Substitution of pre – bronchodilator values as used in normal clinical practice did not change the results. The patients were not randomized to Prednisolone or placebo, so the changed seen after Prednisolone cannot categorically be attributed to this drug. However the data here are a responsible reflection of those likely to appear in clinical practice. Crossover trial of Prednisolone versus placebo have shown a carry. Over effect from Prednisolone to placebo up to 6 weeks.

Patients were recruited because they had a clinical diagnosis of COPD, a history of tobacco smoking, and a broncho dilator response of <10% of predicted despite this, the distribution of response to Prednisolone is wide; 95% of the ex – smokers had an FEV1 response of 412ml or less. Suggesting that changes would need to be greater than this before an alternative diagnosis could be made with any confidence. Whether individuals who exceed these values have bronchial asthma is unlikely to be resolved without pathological studies. Atopy is the moh important identifiable risk factor for the development of asthma. We found no significant difference in the Spiro metric response to Prednisolone between atopic and non – atopic patients, making the unlikely that population continued enough" hidden asthmatics" to influence the overall conclusions.

    These was evidence of a significant regression to the mean effect even using post bronchodilator FEV1 as the out come measure, patients who had the greatest fall in FEV1 following Prednisolone showed the greatest increase before the Prednisolone trial. Similarly patients whose FEV increased mooh after Prednisolone were those who had the greatest deterioration in the 4 weeks before the trial. In an individual patient this change could be sufficiently large to suggest a clinically important benefit when none was present. This makes it difficult to define a subgroup of patients with COPD who are likely to "respond" but, despite this, several attempts to define responder groups have been made. Factious influenced by bronchodilator response and diurnal variation in peak expiratory flow, have generally been included. In carefully population are found no relationship with bronchodilator response. Only one study has developed a discrimination function based on these variables which has been applied to a separate population prospectively and was found to be non – discriminatory. This supports the lack of a true differentiation between steroid responders and non- responders woman appear particularly prone to COPD when exposed to similar amounts of tobacco, but they found no sex difference in Prednisolone responsiveness. Continued smoking reduces the benefits of inhaled corticoids in asthma.. Their data suggest that in COPD this is also true during short term treatment C Oral corticosteroids.

    Corticosteroid trials are advocated as a method of selecting those patients with COPD who might benefit from long corticosteroid treatment. They found no relationship between the short term response to Prednisolone and the rate of duline in FEV1 or health stodes. The only other study that investigated the relationship similarly found no difference ( corticosteroid responders 35ml / year, non responders 29ml/ year while taking inhaled betamethasone diproplonate) our data emphasis that the change in function after corticosteroids is normally distributed and modified by smoking status. Studies in large patients group permit the detection of these effects. But the small signal and relatively large day to day variation in lung function make its accurate detection in routine clinical practice extremely difficult.

    A reduction in exacerbation was the main result at the ISOLDE study. We invested weather this benefit could be predicted by the steroid trial. There was no relationship with steroid response using the ATS definition which requires a minimum change in FEV1 of 200ml, overcoming the confounding effects of low denominator and FEV1 response which can occur using the Callahan definition. As a low FEV1, is associated with a greater exacerbation reduction with inhaled Fluticasone use in this study, and is associated both with exacerbation frequency and a Callahan response, they believe that the results seen using the Callahan criteria were confounded by these relationship. This is supported by the evidence that differences in the response to Prednisolone are largely due to a regression to the mean effect, gather than a trail difference between subjects.

Undertaking corticosteroid trials in patients like these, especially in I care, is not likely to be helpful diagnostically and can be misleading unless the increase in FEV1 following Prednisolone is more than 412ml when and alternative diagnosis could be considered slow decline in health status is not to improve lung function for se although maintenance dose of corticosteroid therapy in COPD is usually recommended, some patience advanced COPD may required maintenance close of corticosteroid therapy in COPD is usually recommended, some patience C advanced COPD may require maintenance dose of oral corticosteroid. In such cases the doses of oral corticosteroids should be kept as low as possible.




    As patience with COPD respond so poor to inhaled corticosteroids, they are commonly prescribed high doses that may be associated with systemic side effects. Patience with COPD may be particularly vulnerable to these systemic effects as they are often elderly, immobile, and have poor nutrition thus increasing the task of developing cataract, glaucoma, diabetes. In a recent large study of inhaled corticosteroids in patients with mild COPD 10% of patients developed skin bruising compared to 4% in the corticosteroids in patients with COPD must weigh the real risk of systematic side effects against the minimal clinical value provided by this treatment.

    1. The protective affects of ICS on the risk of ACUTE MYOCARDIAL INFARCTION for daily medication closes ranging from 50-200 mg of beclomethasone or equivalent. A four higher doses of ICS the risk returned to baseline. It can be explained by anti-inflammatory effects of ICS. Anti-inflammatory actions of inhaled corticosteroids involve the modification of the expression of a wide no of genes, in turn inhibiting the synthesis of cytokines adhesion molecules, enzymes and other proteins involved in inflammation and implicated in pathogenesis of Acute Coronary Syndrome. The lack of benefit at higher closes might plausibly reflect counterbalancing adverse effects on the risk factors. There is a decrease in C - reactive protein itself a marker of increase in risk of acute coronary syndrome, with high doses of ICS over a period of several weeks.

Cataracts: The association between systematic corticosteroids and cataracts, especially at high doses administered for extended period is well documented in both children and adults. Systemic Corticosteroid induced cataract typically is located on the posterior side of the lens and are referred to as posterior sub capsular cataracts.

Ocular Hypertension and open angle glaucoma:

    The risk of increased intra ocular pressure on open angle glaucoma was compared in patients using inhaled corticosteroids and patients not using inhaled corticosteroids. The case control study observed this relationship only among current users of high does of ICS prescribed regularly for 3 or more months. Patients on low to medium doses did not have an increased risk.

    Easy skin bruising is a well recognized Systemic Side effects of ICS therapy, particularly when administered in high doses and to older individuals. Skin bruising also has been found to be associated impairment in adrenal function. Older persons have an increased risk of skin bruising due to age related dermal thinning. The increasingly widespread use of ICS therapy I COPD patients makes it likely that easy defusing will become an even more commonly encountered side effect of ICSs, especially with high does often prescribed for COPD.

    The incidence of Glucocorticoid induced bone loss in COPD has also been reported to be quite high. Bone mineral density, swore of this population was in the range associated with established osteoporosis, while the incidence of vertebral fractures was 29%. It is probable that the incidence and prevalence of Glucocorticoid induced bone loss will increase as the use of chronic oral and high close inhaled GC therapy continues to rise in parallel with the aging of the population at the risk. Glucocorticoid induced bone loss is produced by stimulating osteoclast to mediated bone marrow reception and reducing osteopath medicate bone formation as well as through direct effects on calcium metabolism and sex hormones.



    Treatment with ICS improves FEC, slightly in the First 2-6 months; overall effect of prolonged ICS treatment is not yet clear.
    The randomized placebo-controlled study demonstrated that discontinuation of Fluticusone propionate (1,000 Mg/day) often 4 months of maintenance therapy induced a more rapid onset and higher recurrence – risk of exacerbations in patients with moderate to severe COPD.

    The two earlier studies showing that ICS produce a small initial improvement in FEV1 without additional Function in lung loss in subsequent years. The increased risk of exacerbations after withdrawal of ICS is in accordance and the limited evidence available in the run in phase of the ISOLDE study; ICS were withheld from patients already using these medications. In the flush 7 weeks post withdrawal, 38% of patients previously treated with ICS experience an exacerbation compared with 6% of those who had not received ICS previously, The study by 'O' Brien and Colleagues demonstrated that withdrawal of ICS in elderly patients with COPD led to deterioration in ventilator function and increase exercise induced dyopnoea and showed a trend toward an increased frequency of exacerbation.

    Discontinuation of FP affects distress, due to respiratory symptoms, and disturbance of physical activity, but does not affect the impact on daily living. These findings are in line with the study by Spencer and Colleagues. These results suggest that FP has greatest influenza on deterioration in physical aspects of health rather than psycho social functions.

    The COPD study demonstrate that discontinuation of high doses of FP in patients with moderate to sever COPD induced a more rapid onset and higher risk of exacerbations. However, as 40% of patients have no untoward effect from the withdrawal of ICS there is an urgent need to identify which subgroup of patients & COPD patients responds will to prolonged ICS therapy.



    There is now overwhelming evidence that long term treatment with inhaled corticosteroids provide no significant clinical benefit to patient with COPD. The disease process in COPD appears to be steroid resistant yet patients with COPD are often treated with high doses of ICS for want of any effective therapy in the disease. This must be associated with a high risk of adverse systemic affects and involve unnecessary expense. Inhaled corticosteroids treatment should not be routinely recommended for the management of COPD, unless there is co-existing asthma.

    The Guidelines recommended that in ICS should be prescribed for patience with an FEV1 less than 50%, who have two or more exacerbation, requiring treatment with antibiotics/oral corticosteroids in a 12 months period. The term of treatment is to reduce exacerbation rate & slow decline in health status & not to improve lung function. Although maintenance dose of CS therapy in COPD is usually recommended some patience with Advanced COPD may require maintenance dose of oral corticosteroid. In such case the dose of oral CS should be kept as low as possible.

    There is need for further studies to investigate the efficacy and safety of long term use of ICS for the management of COPD.



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Cite this: U. Santhi Krishna, D. Jyothis, Sijo Pattam, "SAFETY OF INHALED CORTICOSTEROIDS IN COPD", B. Pharm Projects and Review Articles, Vol. 1, pp. 1498-1536, 2006. (

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