Corticosteroids—the synthetic analogs of the glucocorticoid hormones of the adrenal cortex—have emerged as the single most effective class of drugs for treatment of inflammatory diseases. Although it was as early as 1885 that Addison described a “wasting disease” after destruction of the adrenal gland (1), it wasn’t until the 20th century that researchers defined the activity of the adrenal steroids (2). In 1949, Hench et al. introduced corticosteroid treatment for arthritis and other diseases (3,4), which soon expanded to the use of corticosteroids as treatments for nearly all inflammatory diseases. Enthusiasm for systemic corticosteroid therapy waned with the discovery that chronic use caused numerous debilitating adverse effects, but the 1957 introduction of topically active corticosteroids with greatly diminished side effects (5) renewed interest in their widespread use.

Inhaled corticosteroid (ICS) therapy was introduced in the 1970s, initially targeted to patients with severe asthma who required treatment with oral corticosteroids (6,7). Later, ICS therapy was extended to patients for whom sympathomimetics and methylxanthines were ineffective (8), but the major focus was still on patients with severe disease.

The recognition of asthma as an inflammatory disease changed treatment strategy. Reports showing similarities in infiltrations of lymphocytes, mast cells, and eosinophils in the bronchial mucosa, regardless of the severity of asthma (9,10), extended ICS use to populations with only mild persistent disease (11). Clinical reports showing greater reductions in bronchial hyperresponsiveness with the regular use of an ICS in comparison with the regular use of an inhaled β₂ agonist (12,13) added to the impetus. In 1991, the Guidelines for the Diagnosis and Management of Asthma of the National Asthma Education and Prevention Program (NAEPP) recommended ICS therapy for patients with both severe and moderate asthma (14). By 1997, the recommendations also included patients with mild persistent disease (15), and the 2007 Guidelines state that ICSs are the most consistently effective long-term control medications at all steps of care for persistent asthma in both children and adults, regardless of severity (16).

There are two general classes of corticosteroids: mineralocorticoids (MCs) and glucocorticoids (GCs). MCs principally affect the regulation of fluid and electrolyte balance and have no clinical use in the treatment of allergic disease. However, MC activity in corticosteroid medications may produce fluid and electrolyte side effects, so they are not entirely without relevance.

The basic chemical structure of GCs consists of 21 carbon atoms with a total of four rings, three six-carbon rings and a five-carbon ring (17). Hydrocortisone (cortisol) is the parent molecule from which other natural and synthetic GCs derive. Essential features of the anti-inflammatory GC consist of the following: (a) a two-carbon chain at the 17th position, (b) methyl groups at carbons 10 and 13, (c) a ketone oxygen at C3, (d) an unsaturated bond between C-4 and C-5, (e) a ketone oxygen at C-20, and (f) a hydroxyl group at C-11. Modifications of either the nucleus or the side chains produce different GC agents with varying anti-inflammatory and MC activity as compared to cortisol. Further alterations at the C-17 and C-21 positions result in corticosteroids with high topical activity and minimal systemic adverse effects.

Cortisol secretion results from a cascade of stimulatory events in the hypothalamic-pituitary-adrenal (HPA) axis (18). The process begins in the hypothalamus with the secretion of corticotropin-releasing factor (CRF), which stimulates the release of adrenocorticotropic hormone (ACTH), a product of the basophil cells of the anterior pituitary gland. In turn, ACTH
stimulates the production of GCs, which are primarily produced in the zona fasciculata of the adrenal cortex. Cortisol and ACTH secretion normally reaches peak levels in the early morning, then declines throughout the day to a low point in the early-to-late evening (2). Daily secretion of cortisol is about 10 mg to 20 mg (28 μmol to 55 μ (mol), but environmental stress or increased circulating levels of cytokines, such as interleukin (IL)-1, IL-2, IL-6, or tumor necrosis factor-α (TNFα), can raise levels to as high as 400 mg to 500 mg (19).

At least 90% of circulating cortisol is protein-bound, principally to cortisol-binding globulin or transcortin (17). The unbound fraction is biologically active and may bind to transcortin (high affinity/low capacity) or to serum albumin (low affinity/high capacity). Transcortin has a binding capacity of only 0.7 μmol (250 μg) cortisol per liter serum. Thus at low concentrations, approximately 90% of cortisol is plasma-protein-bound, and at higher concentrations of cortisol, transcortin binding becomes saturated. Some synthetic GCs, such as dexamethasone, exhibit little or no binding to transcortin. Because pharmacologic actions, metabolism, and excretion of corticosteroids all relate to unbound steroid concentrations, the binding of circulating steroids to transcortin and albumin play important roles in modifying GC potency, half-life, and duration of effects (2).

The intrinsic pharmacokinetic properties of GCs are described by their volume of distribution (absorption) and clearance (metabolism, half-life, or excretion). Other factors may also include pro-drug conversion by pulmonary esterases to an active GC metabolite. For a specific corticosteroid, bioavailability is also part of the equation (Tables 35.1 and 35.2).

Natural and synthetic steroids are lipophilic compounds readily absorbed after intravenous, oral, subcutaneous, or topical administration. However, lipophilicity varies among preparations. In general, the systemic availability of both oral and intravenous GC preparations is high and is limited by first-pass liver metabolism rather than by incomplete absorption. However, with inhaled GCs, the pharmacokinetic profile and the method of delivery determine the extent and time to systemic absorption of a given GC. A portion of a dose of ICS is swallowed—unless rinsed out—and absorbed from the gastrointestinal (GI) tract. The rest reaches the lower airways and exerts the desired effect. The ratio of desirable/undesirable effects depends on:

Catabolism of corticosteroids is mainly in the liver, although other organs such as the kidney, placenta, lung, muscle, and skin may contribute to the metabolism of endogenous and synthetic GCs. Enzymatic coupling with a sulfate or glucuronic acid forms water-soluble compounds, which leads to renal excretion. There is minimal excretion via the biliary and fecal routes.

As anti-inflammatory agents, GCs exert both direct and indirect inhibitory effects on multiple inflammatory genes (encoding cytokines, chemokines, adhesion molecules, inflammatory enzymes, receptors, and proteins) that have been activated during the inflammatory process (21).

Glucocorticoids diffuse readily across cell membranes and bind to glucocorticoid receptors (GRs) in the cytoplasm (22). The GR is a 94-kD protein which exists in the cytoplasm as a multiprotein complex
containing several heat shock proteins (Hsp90, Hsp70, Hsp56, and Hsp40) (23). These heat shock proteins protect the receptor and prevent its nuclear localization by covering the sites on the receptor that are needed for transport across the nuclear membrane into the nucleus (23). Once corticosteroids have bound to GRs, changes in the receptor structure result in rapid transport of the GR-corticosteroid complex into the nucleus where it binds as a homodimer to specific DNA-binding sites, i.e., glucocorticoid responsive elements (GREs) (24). The relative potency of GCs is dependent on plasma protein-binding, intracellular receptor affinity, and receptor dissociation from activated receptors.

After binding to GREs in the DNA, GCs can promote (transactivate) or inhibit (transrepress) gene expression (25). The number of genes directly regulated by GRs in any given cell is unknown, but studies place the number of steroid-responsive genes per cell at 10 to 100 (26,27). In addition, many genes are indirectly regulated through an interaction with other transcription factors and co-activators. The mechanisms of action of GCs are mediated by genomic effects, secondary nongenomic effects, and interactions with cellular-membrane-bound GRs (28). The classic genomic mechanism of GC action results in the following:

These mechanisms are now thought to be among the most important in explaining GC anti-inflammatory action, but other factors come into play as well. Glucocorticoids hinder the recruitment and activation of T-lymphocytes, eosinophils, dendritic cells, macrophages, and other inflammatory cells, and they inhibit the survival of mast cells at the airway surface, though they do not prevent their activation (29). Airway epithelial cells are likely major targets for inhaled GCs because these cells release numerous inflammatory mediators (29).

Regardless of the route of administration, a general rule of thumb with GC therapy is that clinicians should use the lowest possible effective dose for the shortest time, and patients should undergo frequent reevaluation with the goal of eliminating GCs or reducing dosages. Complications of GC therapy relate to the pharmacology of the agent, dose, dosing interval, and duration of use. Local administration—topical cutaneous or inhaled nasal/bronchial—is recommended where possible to avoid or reduce systemic side effects. These eight broad principles apply: