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= Fluticasone =

Introduction
Steroids are classified into two types - the Corticosteroid and Anabolic Steroids. Corticosteroids are naturally produced in the adrenal cortex and include steroid hormones that the body needs for proper functioning. The corticosteroids are divided into two classes - the glucocorticoids and mineralocorticoids. Corticosteroid medicines are anti-inflammatory drugs that control swelling of the airways to lungs that are in the form of inhalers or intranasal sprays, tablets or oral medications, topical creams and ointments ad as injections. Therefore, they can be used for asthma, skin allergies, arthritis, lupus and more. Fluticasone belongs to the corticosteroids family of medicine, which is a long-acting β2-adrenoreceptor agonist. This drug is used for the management of nasal symptoms of seasonal or perennial, allergic and non-allergic rhinitis in adults and children over the age of 4 years.

Mechanism of action
There are number of studies that show the effects of inhaled glucocorticoids on bronchial inflammation, by performing bronchial biopsies. It is confirmed that treating asthma patients with glucocorticoid reduces the number and activation of inflammatory cells in the airways, as well as improving their lung function. Glucocorticoids work by binding to a specific cytoplasmic glucocorticoid receptor (GR) expressed by most of the cells in the body. Glucocorticoids have been found to inhibit the transcription of most cytokines and chemokines that are relevant in asthma, including IL-1b,TNF-a, GM-CSF, IL-3, IL-4, IL-5, IL-6, IL- 8, IL-11, IL-12, IL-13, RANTES, and macrophage inhibitory protein (MIP)-1a.

In the treatment of allergies, intranasal fluticasone is used to reduce allergic responses of mast cells and eosinophils which are involved in the allergic response by the same cellular mechanism as the topical corticosteroids.

Side effects
Stroids have an affect on most of the organ system. Therefore, the overdose or withdrawal from corticosteroids are followed by a number of serious side effects, some of which could be life-threatening. Therefore, prescribing corticosteroids always requires careful consideration of the relative risks and benefits in each patient. Side effects of fluticasone include headache, sore throat, nosebleeds, nasal burning or nasal irritation, nausea, vomiting, asthma symptoms, or cough. There are no other side effects reported yet.

Safety
Inhaled corticosteroid such as fluticasone, are now seen to have an essential role in the management of asthma in most patients, and has repeatedly been shown to lead to improved control of asthma at all levels of severity. There is growing evidence that inhaled corticosteroid should be used as first-line therapy in both adults and children.

Even though corticosteroid therapy is known to be the most effective way of treating anti-inflammatory asthma, high doses of them in children are still risky. The risk of high doses is compounded in children with concomitant allergic conditions that require multiple forms of topical corticosteroids.

After spraying fluticasone, the majority of drug particles deposit directly in the oropharynx, central airways, or in alveoli, depending on the size of particles as well as the devise. Approximately 10–60% of the inhaled dose is deposited in the lungs which has direct targeted therapeutic effects. The drug molecules then enter the systemic circulation via pulmonary vasculature, leading to potential systemic side effects. The other fraction of the drug molecules (40–90%) deposited in the oropharynx can cause local oropharyngeal side effects. Therefore, the asthma patients are advised to rinse their mouths to remove these deposited particles, but a fraction of the drug molecules could still be absorbed by the GI and go through the first-pass metabolism in the liver. The remaining drug eventually reaches the systemic circulation.

Inhaled corticosteroids have been a key element in the treatment of asthma, but there are some safety issues with the usage of these drugs in patients with stable COPD. Even though an elevated risk of pneumonia with inhaled corticosteroids use has been repeatedly found in studies, the mechanism of action and the effect of the drug in COPD patients are still unclear.

Effect on growth
The risks associated with systemic exposure to inhaled corticosteroids have been studied. Some severe side effects include suppression of hypothalamicpituitary-adrenal (HPA) axis, growth retardation in children, reduction in bone mineral density and osteoporosis, fractures, cataract formation, glaucoma, skin thinning, and easy bruising. Studied also show that patients who use inhaled corticosteroids experience transient non-progressive decreases in growth velocity, but attain normal adult height at later age. Scientists also showed that using inhaled corticosteroids without overdosing or using it long term are unlikely to cause long term or irreversible effects on growth.

Glucocorticoids have been shown to inhibit intestinal calcium absorption, which causes an increase in urinary calcium excretion, and promote bone resorption, leading to a decrease in bone formation and growth.

Corticosteroids can have suppressive effects at every level of a child’s growth system since they are potent inhibitors of linear growth.

Even though the effect of using corticosteroids on a child’s growth has been shown but the mechanism by which it may affect growth is not yet known.

Drug-drug interactions
Ritonavir and Ketoconazole both increase fluticasone levels in the body by eliminating it causing a delay in its metabolism.

Ritonavir is a CYP450 3A4 inhibitor that is used in low doses to pharmacokinetically.

boost levels of other protease inhibitors. Scientists showed that using inhaled fluticasone which is a CYP3A4 substrate with ritonavir result in steroid accumulation, adrenal suppression and Florid Cushing’s syndrome. Common symptoms of Cushing's syndrome include weight gain, hypertension, hyperglycemia, red face, thin skin and short-term memory loss as shown on figure 1. Therefore, regimens containing both fluticasone and ritonavir should be avoided, particularly in patients with end-stage liver disease, since the rate of accumulation of systemic fluticasone may be increased. Ciclesonide and mometasone are also the other two drugs that should not be used with ritonavir due to their pharmacokinetic similarities to fluticasone.

In this review by Foisy and co-workers the interaction of inhaled fluticasone and ritonavir in 25 cases and ritonavir and intranasal fluticasone in three cases showed a significant adrenal suppression. This result followed by other experiments from their paper, proved that the combination of ritonavir and fluticasone should be avoided.

In another study, Kempsford and co-workers co-administered fluticasone and a CYP3A4 inhibitor, ketoconazole, to see its effect on the systemic exposure to fluticasone which resulted in an increase by less than twofold. This result indicates that fluticasone is a substrate of CYP3A which is susceptible to interactions with potent CYP3A inhibitors.