Glucocorticoids beclomethasone dipropionate

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... 

Beclomethasone dipropionate, and several other glucocorticoids—primarily budesonide and flunisolide and mometasone furoate, administered as aerosols—have been found to be extremely useful in the treatment of asthma (see Chapter 20). 

Topical administration to the nose The safety of nasal glucocorticoids in the treatment of allergic rhinitis has been reviewed (434,435). The local application of glucocorticoids for seasonal or perennial rhinitis often results in systemic adverse effects. The use of nasal sprays containing a glucocorticoid that has specific topical activity (such as beclomethasone dipropionate or flunisolide) seems to reduce the systemic adverse effects, but they can nevertheless occur, even to the extent of suppression of basal adrenal function in children (436). Local adverse effects include Candida infection, nasal stinging, epistaxis, throat irritation (437), and, exceptionally, anosmia (438). 

The effects of inhaled glucocorticoids on bone mineral density (measured using dual X-ray absorptiometry of the spine and hip) and biochemical parameters were followed over 18 months. Mean serum osteocalcin concentrations were significantly lower in patients taking beclomethasone dipropionate or budesonide at doses of 800 micro-grams/day and more. However, bone mineral density of the lumbar spine and hip was not affected. The normal advancement of bone mineral density expected in growing children was not affected by inhaled glucocorticoids taken for 7-16 months (SEDA-22,184). 

Comparisons with oral glucocorticoids A meta-analysis of 21 studies in which 810 asthmatic children were treated with oral prednisolone (8 trials) and/or beclomethasone dipropionate, dosage range 200-900 micrograms/day (12 trials) has been reported. Significant suppression of growth occurred with oral glucocorticoids but not with beclomethasone dipropionate (145). 

Beclomethasone dipropionate and several other glucocorticoids—primarily budesonide and flunisolide and mometasone furoate, administered as aerosols—have been found to be effective in the treatment of asthma (see Chapter 20 Drugs Used in Asthma). The switch from therapy with systemic glucocorticoids to aerosol therapy must be undertaken with caution, since manifestations of glucocorticoid deficiency will appear if adrenal function has been suppressed. In such patients, a slow, graded reduction of systemic therapy and monitoring of endogenous adrenal function should accompany the institution of aerosol administration. 

Beclomethasone dipropionate is a corticosteroid with mainly glucocorticoid activity that is started to exert a topical effect on the lungs, without significant systemic activity. It is used by inhalation, generally from a metered-dose aerosol, for the prophylaxis of asthma. Inhalation of nebulized beclomethasone dipropionate has also been used in the management of asthma in children. 

Oral glucocorticoids such as dexamethasone and prednisolone are still used in patients with severe asthma, though these agents are associated with adverse systemic effects. Inhaled glucocorticoid therapy was introduced in 1972 with beclomethasone dipropionate, which dramatically reduced systemic effects. Fluticasone propionate (launched in 1993) is very efficiently inactivated in the liver, and exhibits low oral bioavailability, which in turn leads to a further reduction in systemic exposure. 

Different inhaled glucocorticoids have been compared for their suppressing effects on the hypothalamic-pituitary-adrenal axis (18). In a large meta-analysis, budesonide or beclomethasone dipropionate in doses of over 1500 micrograms/day was associated with adrenal... 

However, the low intrinsic activity of this steroid hindered its widespread use. The glucocorticoid receptor affinity and the topical anti-inflammatory potency of fluocortin butyl (30)are severalfold lower than those of dexa-methasone (126). Fluocortin butyl ameliorated allergic rhinitis at daily doses of 2-8-mg divided into two to four daily inhalations (129, 130), but it did not protect against bronchial obstruction in bronchial provocation tests, even at 8-mg doses divided into four daily inhalations, in contrast to a 10 times lower dose of beclomethasone dipropionate (131). 

Sensory systems Vision In a systematic review of four case-control studies in nearly 200 000 patients, there was a significant relation between cataracts and the dose of inhaled glucocorticoid the random-effects pooled odds ratio for the risk of cataracts per 1000 micrograms increase in daily beclomethasone dipropionate dose was 1.25... 

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. 

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