Inhaled glucocorticoids

Asthma attacks less than twice a week FEV1 >80% Rapid-acting inhaled p2-agonist Low dose inhaled glucocorticoid or cromone (children)... 

Asthma attacks more than twice a week FEV1 60-80% daily use of bronchodilators. Rapid-acting inhaled p2-agonist Inhaled glucocorticoid... 

Glucocorticoids are widely used to treat a variety of inflammatory and immune diseases. With the recognition that airway inflammation is present even in patients with mild asthma, treatment with glucocorticoids is now the mainstay of asthma therapy. Consequently, by far the most common use of glucocorticoids today is in the treatment of asthma and inhaled glucocorticoids have now become established as first-line treatment in adults and children with persistent asthma, the commonest chronic airway inflammatory disease. 

Generally, inhaled glucocorticoids have few side effects, the appearance of which depends on the dose, the frequency of administration, and the delivery system used. The most common side effect is dysphonia (hoarseness), which affects approximately one third of treated patients. Oropharyngeal candidiasis (thrush)... 

Due to the side-effect problems seen with high doses of inhaled glucocorticoids resulting from systemic absorption and the use of oral glucocorticoids in severely affected patients, there has been a search for safer glucocorticoids for inhalation and even for oral administration. As discussed above, a major mechanism... 

G Hochhaus, S Suarez, RJ Gonzalez-Rothi, H Schreier. Pulmonary Targeting of Inhaled Glucocorticoids How Is It Influenced by Formulation Respiratory Drug Delivery VI, Hilton Head, SC, 1998, pp. 45-52. 

Inhaled glucocorticoid preparations, such as be-clomethasone dipropionate and betamethasone valerate, provide an effective alternative to systemic steroids in the treatment of chronic asthma, with lesser side effects than oral or parenteral glucocorticoids (see Chapter 39). In fact, inhaled glucocorticoids have become a mainstay of asthma therapy. Inhalation delivers the agent directly to the target site in relatively low doses, with the potential for more frequent administration. Moreover, inhaled glucocorticoids are metabolized in the lung before they are absorbed, which reduces their systemic effects. However, even modest doses of... 

Based on the concept that asthma is an inflammatory disease that leads to airway obstruction, inhaled glucocorticoids are the first-line treatment for moderate to severe asthma. Inhaled preparations are particularly effective when used to prevent recurrent attacks. This therapy is often combined with an inhaled bron-chodUator such as a p-adrenergic agonist. The use of p-adrenergic agonists or theophylline enables use of a lower dose of glucocorticoid, especially in patients relatively resistant to therapy (see Chapter 39). 

All the glucocorticoids are absorbed from the skin, and are effectively are used as anti-inflammatory drugs. Following oral inhalation, glucocorticoids are absorbed from the gastrointestinal and respiratory tracts. 

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... 

Local adverse effects are common in patients with asthma who use inhaled glucocorticoids, as suggested by a survey of the prevalence of throat and voice symptoms in patients with asthma using glucocorticoids by metered-dose pressurized aerosol (SEDA-20, 369 35). 

Oral candidiasis is seen in some 5-10% of patients who use inhaled glucocorticoids, particularly when oral hygiene is poor, but is rarely symptomatic. The risk can be reduced by the use of a large-volume spacer (141,142). 

Accelerated bone loss, with an increased risk of first hip fracture, occurred in elderly women taking oral glucocorticoids (201). At baseline, 122 (1.5%) women were taking inhaled glucocorticoids only (median dose equivalent to... 

Primary esophageal histoplasmosis must be considered in patients who have a history of gastroesophageal reflux disease and are immunosuppressed by long-term glucocorticoids (SEDA-22,450 333). Oropharyngeal candidiasis is a well-described adverse effect of inhaled glucocorticoids. However, few cases of esophageal candidiasis have been reported (SEDA-22,179). 

Mortality associated with glucocorticoid has been retrospectively studied in 556 patients with chronic obstructive pulmonary disease admitted to a rehabilitation center (353). Median survival was 38 months and 280 patients died during follow-up. On multivariate analysis, oral glucocorticoid use at a prednisone equivalent of 10 mg/day without inhaled glucocorticoid was associated with an increased risk of death (RR = 2.34 95% Cl = 1.24, 4.44), and 15 mg/day increased the risk further (RR = 4.03 95% Cl = 1.99, 8.15). The risk of death was not increased in those using 5 mg/day or when patients used any oral dose in combination with inhaled glucocorticoids. 

Most knowledge of the adverse effects of glucocorticoids has been acquired in connection with their use as oral products. However, various other routes of administration have been developed, sometimes specifically in the hope of securing a local therapeutic effect while avoiding systemic adverse reactions. Although experience has shown that the latter cannot be eliminated in this way, they can be diminished in some cases. In other cases, new problems arise. Administration by inhalation is covered in the monograph on inhaled glucocorticoids. 

Systemic availability of inhaled glucocorticoids can be reduced in two ways. First, by using esters that reduced local absorption in the case of beclomethasone the dipropionate is used. Secondly, by using glucocorticoids that are extensively metabolized in the liver after absorption from the gut, such as fluticasone and budesonide. These strategies can be combined fluticasone is given as the ester fluticasone propionate. 

The systemic availability of an inhaled glucocorticoid represents the additive and complex combination of pulmonary and gastrointestinal drug absorption. Absorption is influenced by many factors, including delivery device, the use of a spacer, the particle size of the inhaled drug, and the absorption and metabolism of the swallowed drug (1). 

In healthy volunteers, high doses of both budesonide and fluticasone were readily absorbed after inhalation from a mete red-dose aerosol (2). Fluticasone is extensively metabolized by the liver, so measurable concentrations of parent drug in the systemic circulation reflect efficient absorption across the lung. Lower doses of these inhaled glucocorticoids also result in some systemic absorption, reflected in effects on the hypothalamic-pituitary-adrenal axis (3). 

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