17.01.5.1 Glucocorticoids

The glucocorticoids have been previously discussed as drugs that have effects mediated by intracellular receptors (eChapter 3). The endogenous and synthetic glucocorticoids readily get into the cytoplasm of all cells, but only some of the cells have receptors for the glucocorticoids. When the glucocorticoid is bound to the receptor, it moves to the nucleus, and protein synthesis is initiated. Some of the proteins synthesized have anti-inflammatory actions.

There are many components to inflammation including the synthesis of prostaglandins, leukotrienes, cytokines, adhesion molecules and the release of histamine and leukotrienes, and all of these components are inhibited by the glucocorticoids (Figure 17.3).

Figure 17.3 Components of inflammation inhibited by the glucocorticoids

The glucocorticoids commonly used in asthma include beclomethasone, fluticasone and budesonide. All are inhaled. One problem with inhalation is that the glucocorticoid deposited in the mouth can lead to reduced immunity, and candidiasis (thrush) can develop. This can be minimised by using a spacer and by washing out the mouth and throat after using a glucocorticoid inhaler. The glucocorticoids are prophylactic (preventative) in the treatment of asthma. They cause an improvement in symptoms, so that there are less attacks of asthma, and this can be demonstrated by a reduced use of short-acting b-adrenoceptor agonists in subjects that take prophylactic glucocorticoids.

As drug delivery by inhalation, not only delivers drug to the lungs, but also to the gastrointestinal tract, the glucocorticoids for asthma have been designed to limit systemic effects. Thus, beclomethasone crosses membranes poorly, which means it has limited absorption from the lung and gastro-intestinal tract, and limited systemic side effects.

In contrast, fluticasone and budesonide are well absorbed from lung and the gastrointestinal tract (Figure 17.3). Any fluticasone or budesonide absorbed from the lung is readily metabolised by the liver. When swallowed, fluticasone and budesonide have extensive first pass liver metabolism, which limits access to the circulation and decreases the risk of systemic side effects (Figure 17.4).

Figure 17.4 Fate of fluticasone and budesonide (Copyright QUT, Sheila Doggrell)

When there are acute exacerbations of asthma, it may be necessary to use systemic prednisone to overcome asthma. Prednisone is more potent than beclomethasone or budesonide as an anti-inflammatory. However, the systemic use of prednisone must be short-term use to prevent systemic adverse effects.

Glucocorticoids are also used in the treatment of COPD, where they give only a little benefit. Nevertheless they are used as there are no medicines that give a major benefit in COPD.

In addition to being anti-inflammatory agents, the endogenous glucocorticoids have lots of other effects in the body, and these are mimicked or exaggerated by the more potent glucocorticoids used as medicines. Administered glucocorticoids mimic the endogenous glucocorticoids to turn off the hypothalamus-pituitary-adrenal axis. With the long term systemic use (Table 17.1), the administration of systemic glucocorticoids causes suppression of the axis, which is slow to reverse. Thus, after long term systemic use, glucocorticoids have to be withdrawn slowly or there will be major problems due to the lack of the endogenous compounds produced by the axis. This means that even if there are severe detrimental effects, which there can be with the glucocorticoids, they cannot be withdrawn immediately. With the inhalation of beclomethasone or budesonide, or the short-term use of oral prednisone, there is no suppression of the hypothalamus-pituitary-adrenal axis. However, this can occur if high doses of the inhaled glucocorticoids are used.

Most people with asthma take a glucocorticoid to prevent the inflammatory component of asthma and a long acting β-adrenoceptor agonist (LABA). For ease of use, salmeterol is often used in combination with a glucocorticoid in a single inhaler. Using one inhaler for both the glucocorticoid and LABA, instead of two inhalers, increases the adherence to the medication, and reduces the exacerbations of asthma.

Table 17.1 Adverse effects with glucocorticoids

With long term systemic used of glucocorticoids, growth retardation in children may occur, but this has not been reported with inhalation of glucocorticoids. The glucocorticoids promote bone resorption, and this leads to osteoporosis (thinning of the bone) and osteonecrosis (breakdown of bone). Osteoporosis is observed with the long term systemic used of glucocorticoids, but is relative modest with inhalation or short term use of the glucocorticoids. The glucocorticoids have major effects on both carbohydrate and lipid metabolism leading to hyperglycaemia and fat redistribution. This is a major problem with the systemic long term use of glucocorticoids but only a minor problem with inhaled or short term use of oral glucocorticoids. Long term glucocorticoid use is associated with cataracts, but this is unproven with inhaled or short term use of oral glucocorticoids. Systemically administered glucocorticoids cause skin thinning, but this is only observed with long term use of high doses of inhaled steroids.