Fluticasone, asthma

Prednisone Like fluticasone Like fluticasone Asthma adjunct in COPD Oral duration 12-24 hours Toxicity Multiple t see Chapter 39... 

Asthma is a chronic inflammatory disease. Therefore steroids represent the most important and most frequently used medication. Already after the fust treatment, steroids reduce cellular infiltration, inflammation, and the LAR, whereas changes in the EAR require prolonged treatment to lower the existent IgE levels. The mechanisms of steroid actions are complex and only incompletely understood. Besides their general antiinflammatory properties (see chapter glucocorticoids), the reduction of IL-4 and IL-5 production from T-lymphocytes is particularly important for asthma therapy. The introduction of inhaled steroids, which have dramatically limited side effects of steroids, is considered one of the most important advancements in asthma therapy. Inhaled steroids (beclomethasone, budesonide, fluticasone, triamcinolone, momethasone) are used in mild, moderate, and partially also in severe asthma oral steroids are used only in severe asthma and the treatment of status asthmaticus. Minor side effects of most inhaled steroids are hoarseness and candidasis, which are avoided by the prodrug steroid ciclesonide. 

Inhaled steroids (commonly used are beclomethasone, budesonide, triamcinolone, fluticasone, flunisolide) appear to attenuate the inflammatory response, to reduce bronchial hyperreactivity, to decrease exacerbations and to improve health status they may also reduce the risk of myocar dial infar ction, but they do not modify the longterm decline in lung function. Whether- steroids affect mortality remains unclear. Many patients appear to be resistant to steroids and large, long-term trials have shown only limited effectiveness of inhaled corticosteroid ther apy. Certainly, the benefit from steroids is smaller in COPD than in asthma. Topical side-effects of inhaled steroids are oropharyngeal candidiasis and hoarse voice. At the normal doses systemic side-effects of inhaled steroids have not been firmly established. The current recommendation is that the addition of inhaled gluco-coiticosteroids to bronchodilator treatment is appropriate for patients with severe to veiy sever e COPD. 

Cater, J.I., Vare, M., Peters, W.J., Olsson, B., and Gomez, E., Comparison of the efficacy of fluticasone propionate given twice daily via the Diskus /Accuhaler and the Diskhaler in patients with asthma, Eur. Resp. J., 8 427S (1995). 

Fluticasone is a potent corticosteroid that is available as a nasal spray indicated in allergic rhinitis (hay fever) and as an inhaler used in asthma. 

Recommended Starting Doses of Fluticasone Propionate/Salmeterol for Asthma Patients (Age 12) Taking Inhaled Corticosteroids ... 

Drake AJ, Howells RJ, Shield JPH, PrendiviUe A, Ward PS, Crowne EC. Symptomatic adrenal insufficiency presenting with hypoglycaemia in asthmatic children with asthma receiving high dose inhaled fluticasone propionate. BMJ 2002 324 1081-2. 

Bateman ED, Jacques L, Goldfrad C, Atienza T, Mi-haescu T, Duggan M. Asthma control can be maintained when fluticasone propionate/sahneterol in a single inhaler is stepped down. J AUergy Clin Immunol 2006 117(3) 563-70. 

Woodcock AA, Bag donas A, Boonsawat W, Gibbs MR, Bousquet J, Bateman ED. GOAL Steering Committee and Investigators. Improvement in asthma endpoints when aiming for total control sahneterol/fluticasone propionate versus fluticasone propionate alone. Prim Care Respir J 2007 16(3) 155-61. 

The corticosteroids are effective in most children and adults with asthma. They are beneficial for the treatment of both acute and chronic aspects of the disease. Inhaled corticosteroids, including triamcinolone ace-tonide (Azmflcort),beclomethasone dipropionate (Beclo-vent, Vancerit), flunisolide AeroBid), and fluticasone (Flovent), are indicated for maintenance treatment of asthma as prophylactic therapy. Inhaled corticosteroids are not effective for relief of acute episodes of severe bronchospasm. Systemic corticosteroids, including prednisone and prednisolone, are used for the short-term treatment of asthma exacerbations that do not respond to (32-adrenoceptor agonists and aerosol corticosteroids. Systemic corticosteroids, along with other treatments, are also used to control status asthmaticus. Because of the side effects produced by systemically administered corticosteroids, they should not be used for maintenance therapy unless all other treatment options have been exhausted. 

A fixed combination of inhaled fluticasone and sal-meterol (Advair) is available for maintenance antiinflammatory and bronchodilator treatment of asthma. 

More recently, compounds bearing a second fluorine atom in position 6 (generally with ot configuration) have been developed (fluprednisolone). The introduction of this second fluorine atom can be performed by different pathways opening of 5,6-oxirane by HF, or electrophilic fluorination of dienol derivatives (cf. Figure 8.33, Chapter 8). " The fluorine in position 9 is introduced by means of the Fried method. These derivatives, substituted in both positions 6 and 9, are used in the treatment of asthma and allergy (fluocinolone, diflorasone, fluticasone cf. Chapter 8). 

Treatment with omalizumab, the monoclonal humanized anti-IgE antibody, is reserved for patients with chronic severe asthma inadequately controlled by high-dose inhaled corticosteroid plus long-acting B-agonist combination treatment (eg, fluticasone 500 meg plus salmeterol 50 meg inhaled twice daily). This treatment reduces lymphocytic, eosinophilic bronchial inflammation and effectively reduces the frequency and severity of exacerbations. It is reserved for patients with demonstrated IgE-mediated sensitivity (by positive skin test or radioallergosorbent test [RAST] to common allergens) and an IgE level within a range that can be reduced sufficiently by twice-weekly subcutaneous injections. 

Fluticasone Alters gene expression Reduces mediators of inflammation powerful prophylaxis of exacerbations Asthma adjunct in COPD Aerosol duration hours Toxicity Limited by aerosol application candidal infection, vocal cord changes... 

The first inhaled glucocorticoid, beclomethasone dipropionate, revolutionized asthma therapy, when it was found that topical delivery to the lung resulted in reduced systemic side-effects (adrenal suppression, oseteoporosis and growth inhibition) typically seen with oral steroid treatments. Interestingly, a further reduction in systemic exposure was achieved with the introduction of fluticasone propionate (1). The evolution of this drug stemmed from observations with the steroid 17-carboxylates that showed that these esters were active topically when esterified, while the parent acids were inactive. Thus it was realized that enzymatic hydrolysis of the ester would lead to systemic deactivation. SAR studies led to a series of carbothioates, which were very active in vivo when topically applied to rodents, but were inactive after oral administration. It was shown that fluticasone propionate (1) underwent first pass metabolism in the liver to the corresponding inactive 173-carboxylic acid (la) (Scheme 1). This observation was... 

A 23-year-old man, with a history of asthma, house dust mite allergy, and rhinoconjunctivitis, presented with acute respiratory symptoms. He was given oral cetirizine, inhaled salmeterol, and fluticasone propionate, and oral prednisone 40 mg/day for 1 week and 20 mg/day for 1 week. His asthma recurred when prednisone was withdrawn and he took oral prednisone 60 mg/day for 1 week and 40 mg/day for 1 week. He also took montelukast 10 mg/day. He then developed severe peripheral edema with a gain in weight of 13 kg. Prednisone was withdrawn and his edema resolved. Montelukast was continued. 

Whitaker K, Webb J, Barnes J, Barnes ND. Effect of fluticasone on growth in children with asthma. Lancet 1996 348(9019) 63-4. 

The effect of increasing doses of mometasone furoate and fluticasone propionate by dry powder inhaler on adrenal function was studied by using overnight urinary cortisol in 21 patients with asthma (55). Patients were randomized in a crossover fashion to receive 2-weekly consecutive doubling doses of either fluticasone propionate (500, 1000, and 2000 micrograms/day) or mometasone furoate (400, 800, and 1600 micrograms/day). Both treatments were... 

A 32-year-old woman s asthma regimen was changed from budesonide to fluticasone propionate 500 micrograms/day and salmeterol (44). Eight months later, she was evaluated because of excessive bodyweight gain her serum cortisol concentration was 16 nmol/1. Fluticasone propionate was replaced with nedocromil and 1 month later her serum cortisol concentration had normalized. 

The efficacy and safety of fluticasone 750 micrograms/ day and beclomethasone 1500 micrograms/day delivered by a spacer device have been compared in 30 asthmatic children in a 12-week, randomized, double-blind, crossover study (118). All of the children had persistent asthma requiring 1000-2000 micrograms/day of inhaled glucocorticoids before the trial. There was no significant... 

Cushing s syndrome occurred in a 44-year-old HIVpositive patient who used inhaled fluticasone (500 micrograms qds) for severe asthma for 2 years (153). Stavudine and nevirapine were replaced by abacavir and ritonavir + lopinavir and 2 months later he developed the typical features of Cushing syndrome. 

Brutsche MH, Brutsche IC, Munawar M, Langley SJ, Masterson CM, Daley-Yates PT, Brown R, Custovic A, Woodcock A. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers a randomised crossover study. Lancet 2000 356(9229) 556-61. 

Berend N, Kellett B, Kent N, Sly PD, Bowler S, Burdon J, Dennis C, Gibson P, James A, Jenkins C. Collaborative Study Group of the Australian Lung Foundation. Improved safety with equivalent asthma control in adults with chronic severe asthma on high-dose fluticasone propionate. Respirology 2001 6(3) 237-46. 

Eid N, Morton R, Olds B, Clark P, Sheikh S, Looney S. Decreased morning serum cortisol levels in children with asthma treated with inhaled fluticasone propionate. Pediatrics 2002 109(2) 217-21. 

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