Identification and source

Corticosteroids are a group of chemicals secreted by the adrenal cortex and are referred to as adrenal cortical hormones. The adrenal or suprarenal gland is composed of two portions (Figure 11-1). The inner zone is the adrenal medulla and produces epinephrine. The outer zone is the cortex, which is the source of corticosteroids. Three types of corticosteroid hormones are produced by the adrenal cortex: glucocorticoids (e.g., cortisol), mineralocorticoids (e.g., aldosterone), and sex hormones (e.g., androgens and estrogens). The mineralocorticoid aldosterone regulates body water by increasing the amount of sodium reabsorption in the renal tubules. The corticosteroids used in pulmonary disease are all analogues of cortisol, or hydrocortisone as it is also termed. Glucocorticoid agents are referred to as glucocorticosteroids and by the more general term corticosteroid, or simply as steroids.

Hypothalamic-pituitary-adrenal axis

The side effects of corticosteroids and the rationale for aerosol or alternate-day therapy can be understood if the production and control of endogenous (the body’s own) corticosteroids are grasped. The pathway for release and control of corticosteroids is the hypothalamic-pituitary-adrenal (HPA) axis (Figure 11-2). Stimulation of the hypothalamus causes impulses to be sent to the area known as the median eminence, where corticotropin-releasing factor (CRF) is released. CRF circulates through the portal vessel to the anterior pituitary gland, which then releases corticotropin, or adrenocorticotropic hormone (ACTH), into the bloodstream. ACTH in turn stimulates the adrenal cortex to secrete glucocorticoids, such as cortisol. Cortisol and glucocorticoids in general regulate the metabolism of carbohydrates, fats, and proteins, generally to increase levels of glucose for body energy. This is the reason cortisol and its analogues are called glucocorticoids. They can also cause lipolysis, redistribution of fat stores, and breakdown of tissue protein stores. These actions are the basis for many of the side effects seen with glucocorticoid drugs. The breakdown of proteins for use of the amino acids (gluconeogenesis) is responsible for muscle wasting, and the effects on glucose metabolism can increase plasma glucose levels. The latter is sometimes referred to as steroid diabetes.⁴

Hypothalamic-pituitary-adrenal suppression with steroid use

One of the most significant side effects of treatment with glucocorticoid drugs (exogenous corticosteroids) is adrenal suppression or, more generally, HPA suppression. When the body produces endogenous glucocorticoids, there is a normal feedback mechanism within the HPA axis to limit production. As glucocorticoid levels increase, release of CRF and ACTH is inhibited, and further adrenal production of glucocorticoids is stopped. This feedback inhibition of the hypothalamus and the pituitary is shown in Figure 11-2 and is analogous to the servo mechanism by which a thermostat regulates furnace production of heat by monitoring temperature levels.

The body cannot distinguish between its own endogenous glucocorticoids and exogenous glucocorticoid drugs. Administration of glucocorticoid drugs increases the body’s level of these hormones, and this inhibits the hypothalamus and pituitary glands, which decreases adrenal production. This inhibition is referred to as HPA suppression or, specifically, adrenal suppression. It is seen with systemic administration of corticosteroids, begins after 1 day of treatment, and is significant after 1 week of oral therapy at usual doses. A primary reason for using aerosolized glucocorticoids is to minimize adrenal, or HPA, suppression by minimizing the dosage and localizing the site of treatment.

If a patient has received oral corticosteroids and adrenal suppression has occurred, weaning from the exogenous corticosteroids through use of tapered dose therapy allows time for recovery of the body’s own adrenal secretion. It should be noted that aerosolized corticosteroids do not deposit sufficient amounts of drug to replace the missing output of a suppressed adrenal gland. Therefore, a patient with adrenal suppression cannot be abruptly withdrawn from oral corticosteroids and placed on an aerosol dosage. The aerosol should be started while the oral agent is tapered off slowly at the same time.

Diurnal steroid cycle

The production of the body’s own glucocorticoids also follows a rhythmic cycle, termed a diurnal or circadian rhythm. This daily rise and fall of glucocorticoid levels in the body are shown in Figure 11-3. On a daily schedule of daytime work and nighttime sleep, cortisol levels are highest in the morning around 8 am. These high plasma levels inhibit further production and release of glucocorticoids and ACTH by the HPA axis because of the feedback mechanism previously described. During the day, plasma levels of ACTH (see Figure 11-3, dotted line) and cortisol (see Figure 11-3, solid line) gradually decrease. As the glucocorticoid level decreases, the anterior pituitary is reactivated to begin releasing ACTH, which stimulates production of cortisol by the adrenal cortex. This lag between increased ACTH and cortisol levels is illustrated in Figure 11-3. One of the reasons for jet lag and the delay in adjusting to night shift from day shift is that this diurnal and regular rhythm of corticosteroid levels becomes out of synchronization with the time zone and the work time. Although a worker needs to sleep at 8 am. after working all night, the body is wide awake, with energy stores being released.

Alternate-day steroid therapy

Alternate-day therapy mimics the natural diurnal rhythm by giving a steroid drug early in the morning, when normal tissue levels are high. Suppression of the HPA system occurs at the same time it normally would with the body’s own steroid, and on the alternate day the regular diurnal secretion in the HPA system can resume. Tissue side effects are minimized because the drug is administered at the time when tissues are normally exposed to elevated corticosteroid levels by the body’s rhythm. Use of an intermediate-acting corticosteroid drug, with a duration of 12 to 36 hours, allows drug therapy to be restricted to alternate days.

Inflammation in the airway

Inflammation can occur in the lungs in response to various causes, including direct trauma (gunshot wound, stabbing), indirect trauma (blunt chest injury), inhalation of noxious or toxic substances (chlorine gas, smoke), respiratory infections and systemic infections producing septicemia and septic shock with acute respiratory distress syndrome (ARDS), and allergenic or nonallergenic stimulation in asthma. The two most common inflammatory diseases of the airway seen in respiratory care are chronic bronchitis, usually caused by tobacco smoking, and asthma, which can be caused by a range of triggers and involves a complex pathophysiology.

Because glucocorticoids are a mainstay for treating asthma, the multiple pathways and mediators for the genesis of airway inflammation seen in asthma are briefly described. Asthma is currently understood as a disease in which there is chronic inflammation of the airway wall, causing airflow limitation and a hyperresponsiveness to various stimuli (Box 11-1).^4,5 The airway inflammation is mediated by inflammatory cells, such as mast cells, eosinophils, T lymphocytes, and macrophages. The mast cell and the eosinophil are considered to be the major effector cells of the inflammatory response, regardless of whether the asthma is allergic or nonallergic.⁶ T lymphocytes may be pivotal in coordinating the inflammatory response by release of numerous proinflammatory cytokines (proteins that regulate immune/inflammatory responses), which act on basophils, epithelial cells, and endothelial cells in the airway to further the inflammatory process. The potent mediators released during an asthmatic reaction cause airway smooth muscle contraction (bronchospasm), increased microvascular leakage and airway wall swelling, mucus secretion, and remodeling of the airway wall over the longer term. In an acute state, people with asthma exhibit wheezing, breathlessness, chest tightness, and cough, especially at night or early morning. The acute symptoms produced by the airway inflammation are at least partly reversible either spontaneously or with pharmacologic treatment. Treatment with antiinflammatory agents such as glucocorticoids is important to reduce the basal level of airway inflammation and reduce airway hyperresponsiveness and the predisposition to acute episodes of obstruction.

Asthmatic reactions are biphasic, including an early phase and a late phase. Figure 11-4 shows a conceptual representation of the overall process. After an insult to the asthmatic airway by an allergen, cold air, viral infection, or noxious gas, there is evidence that the early asthmatic response is caused by immunoglobulin E (IgE)–dependent activation of airway mast cells, which can release inflammatory mediators such as histamine, prostaglandin D₂ (PGD₂), and leukotriene C₄.⁵ The immediate response of the airway to chemicals such as histamine is bronchospasm. This response peaks at about 15 minutes and then declines over the next hour; this produces the early phase decrease in expiratory flow rates illustrated in Figure 11-4.

Although the early bronchoconstriction of smooth muscle may self-limit or respond to β agonists, the progression of cellular events can continue. Mast cell mediators and the release of cytokines recruit other inflammatory cells (eosinophils, basophils, monocytes/macrophages, and lymphocytes) by activating epithelial cells and endothelial cells to release adhesion molecules (e.g., intercellular adhesion molecule [ICAM]) and other cytokines to cause the late phase reaction. During the late phase response, mast cells and recruited eosinophils, lymphocytes, or macrophages that have infiltrated the airway release a range of inflammatory mediators. Neutrophils are not generally associated with asthma and allergic reactions in the absence of infection. The late asthmatic response occurs 6 to 8 hours after a challenge, and it may last for 24 hours. The late-phase reaction is thought to be reflective of the chronic inflammation characterizing asthma between acute episodes.⁶

Phospholipids in the cell membrane of mast cells and other cells are converted by phospholipase A₂ to arachidonic acid and then to various bronchoactive and vasoactive substances by the two metabolic paths shown in Figure 11-4: the cyclooxygenase and lipoxygenase pathways. The term eicosanoid is used to refer to the products of the two pathways. The migration of eosinophils and lymphocytes and further development of inflammation-producing chemicals such as the arachidonic acid metabolites and cytokines all contribute to build an inflammatory response in the lung.⁷ In addition to smooth muscle spasm, mucus secretion occurs, along with mucosal swelling resulting from increased vascular permeability. Shedding of airway cells (desquamation) and goblet cell hyperplasia are seen. The result is mucous plugging of the airway, complicated by the cellular debris in the bronchial lumen. The pathology of bronchial asthma has been described as “chronic desquamating eosinophilic bronchitis.”⁸ These airway changes lead to further bronchial hyperreactivity seen in asthma. There is evidence of airway remodeling, with increased tenascin (an extracellular matrix protein for cell development), collagens, and fibronectin, all of which can cause thickening of the basement membrane in the airway wall. This airway remodeling deregulates communication between cells, promoting epithelial damage and enhancing the inflammatory response.⁹

Aerosolized corticosteroid agents

Several aerosol steroid agents, all of which are glucocorticoids, are available for inhalational use in the United States at the time of this edition. These are identified in Table 11-1, which summarizes steroids used for oral inhalation, and Table 11-2, which lists agents for intranasal delivery, giving strengths and recommended doses. Originally, in the United States, all of the orally inhaled corticosteroids were available as metered dose inhaler (MDI) formulations. Three dry powder inhalers (DPIs), Diskus (fluticasone), Pulmicort Flexhaler (budesonide), and Asmanex Twisthaler (mometasone furoate), have also been introduced, along with the only approved small volume nebulizer (SVN) formulation (budesonide [Pulmicort Respules]). At the time of this edition, all of the MDI formulations are available with hydrofluoroalkane (HFA) propellant (beclomethasone, flunisolide, fluticasone, and ciclesonide) with the exception of triamcinolone. Azmacort (triamcinolone) inhaler was discontinued as of December 31, 2010.

These agents possess a high topical-to-systemic potency ratio, which makes them suitable for control of asthma or COPD with minimal systemic side effects. The chemical structures of the aerosol agents available for oral and nasal inhalation are shown in Figure 11-5. Each of the aerosol agents is briefly described next.

Intranasal corticosteroids

All of the steroids available as orally inhaled agents are also available in an intranasal formulation. Exact indications for the intranasal preparations vary by specific agent, but intranasal steroids generally are used to treat allergic or inflammatory nasal conditions and seasonal or perennial allergic or nonallergic rhinitis and to prevent recurrence of nasal polyps. Available preparations are listed in Table 11-2, with strengths and recommended doses. Other agents that are used to treat seasonal allergic rhinitis include H₁-receptor antagonists (e.g., loratadine), cromolyn sodium (see Chapter 12), topical vasoconstrictors such as oxymetazoline or ephedrine, and anticholinergics such as ipratropium bromide.

Mode of action

Glucocorticoids are highly lipophilic and enter airway cells to bind to intracellular receptors.²⁴ This mechanism of drug signaling action was described briefly in Chapter 2 in the discussion of the pharmacodynamics of lipid-soluble drugs that interact with intracellular receptors. Originally, investigators thought that corticosteroids or, more simply, steroids exerted antiinflammatory activity by stabilizing lysosomes within neutrophils; this prevented degranulation and an inflammatory response. In the mid-1960s, steroid receptors were discovered, and it was realized that steroids modify the inflammatory response by inducing gene expression within the cell. By the 1980s, it was shown that glucocorticoids induce gene expression for the antiinflammatory protein lipocortin, which inhibits the enzyme phospholipase A₂ (PLA₂), preventing the arachidonic acid cascade, which leads to prostaglandin synthesis and lipoxygenase products. However, now it is understood that PLA₂ inhibition is only one of multiple mechanisms by which steroids attenuate the inflammatory response.^6,25–27

Steroids suppress a local or systemic inflammatory response by at least three general actions; these actions are illustrated in Figure 11-6. Generally, steroids diffuse into the cell and bind to a glucocorticoid receptor. Before binding by a steroid, the glucocorticoid receptor is in an inactive state and is bound to a protein complex termed heat shock protein 90 (hsp90), which prevents the unoccupied receptor from translocating to the nucleus of the cell. When the steroid binds to the receptor, hsp90 dissociates, and the steroid-receptor complex translocates to the cell nucleus. One general action (not always the first temporally) of a glucocorticoid is to upregulate the transcription of antiinflammatory genes for substances such as lipocortin, previously described.^25–27 In the nucleus, the steroid produces this part of its effect on the cell by binding to portions of the nuclear DNA termed glucocorticoid response elements. Binding of the drug-receptor complex to glucocorticoid response elements upregulates, or induces, transcription of antiinflammatory substances such as lipocortin, neutral endopeptidase, secretory leukocyte protease inhibitor (SLPI), or inhibitors of plasminogen activator.⁶ These are all antiinflammatory substances. A second general action of glucocorticoids is the suppression of factors such as activator protein-1 (AP-1) and nuclear factor-κB (NF-κB), which cause transcription of genes involved in inflammation. This suppression may be by means of a direct interaction with these transcription factors, by which the transcription factor is inactivated before it induces gene expression in the nucleus.²⁵ Direct inactivation of AP-1 and NF-κB leads to downregulation of gene expression for proinflammatory mediators such as cytokines. NF-κB regulates genes that have increased expression in asthma, including genes for cytokines such as interleukins (e.g., interleukin-1 [IL-1], interleukin-3 [IL-3]); chemokines; tumor necrosis factor-α (TNF-α); nitric oxide synthase, which produces nitric oxide in the airway; and adhesion molecules, which promote recruitment and attachment of leukocytes (eosinophils and basophils) from the circulation to the airway endothelium.^14,25,26 A direct inactivation of inflammatory transcription factors such as AP-1 or NF-κB may account for the rapidity with which some cellular effects of steroids are seen and that are not well explained by the time needed for modification of gene expression within a cell. A third action of glucocorticoids is to upregulate the expression of inhibitors of NF-κB, such as the inhibitor protein IκBα. This inhibitor of NF-κB further suppresses gene expression for proinflammatory proteins, such as cytokines.^26–28

The general result of these actions is to induce gene expression for antiinflammatory proteins and receptors and to suppress gene expression for proinflammatory proteins. Overall, glucocorticoids inhibit the cytokine production responsible for recruitment and migration of inflammatory cells such as eosinophils and lymphocytes into the airway. Examples of cytokines that are suppressed through gene suppression activity of steroids are listed in Box 11-2.

Glucocorticoids inhibit many of the cells involved in airway inflammation, including macrophages, T lymphocytes, eosinophils, and mast cells in the bronchial airway epithelium and submucosa, and reverse the shedding of epithelial cells and goblet cell hyperplasia seen in asthma.^25,30 By decreasing cytokine-mediated survival of eosinophils, apoptosis of eosinophils occurs, reducing the number of eosinophils in the circulation and in the airway of subjects with asthma. Glucocorticoids also reduce the number of mast cells within the airways; mast cells are sources of histamine and other mediators of inflammation and inhibit plasma exudation and mucus secretion in inflamed airways.^24,29

Effect on white blood cell count

Leukocytes, such as monocytes, macrophages, neutrophils, and basophils, are also essential to the inflammatory response and are attracted to an area of injury by the chemotactic factors identified among the mediators of inflammation. Neutrophils usually adhere (“marginate”) to the capillary endothelium of storage sites in the lung. Glucocorticoids cause depletion of these stores and reduce their accumulation at inflammatory sites and in exudates. This is termed demargination and can increase the number of neutrophils in circulation as the cells leave their storage sites. An overall increase in the white blood cell count can be seen in patients receiving glucocorticoids. Glucocorticoids affect other leukocytes by inhibiting the number of monocytes, basophils, and eosinophils; this can also be seen in the differential count of these cells. A person with allergic asthma who would otherwise have a higher than normal eosinophil count would show a low count after initiation of drug therapy. Finally, glucocorticoids constrict the microvasculature to reduce leakage of the above-cited cells and fluids into inflammatory sites.

Effect on β receptors

β-adrenergic agents are among the most potent inhibitors of mast cell release, yet an individual with asthma in an acute episode may be unresponsive to these drugs. A beneficial effect of glucocorticoids is their ability to restore responsiveness to β-adrenergic stimulation.^23,30 This effect can be seen within 1 to 4 hours after intravenous administration of glucocorticoids and is the rationale for administering a bolus of steroid in status asthmaticus as part of acute treatment. Although steroid action is slow, the sooner steroids are given, the sooner the asthmatic begins to respond to β-adrenergic drugs, and supported ventilation may be avoided. Glucocorticoids enhance β-receptor stimulation by increasing the number and availability of β receptors on the cell surfaces and by increasing affinity of the receptor for β agonists. There is also evidence that glucocorticoids prolong endogenous circulatory catecholamine action by inhibiting the uptake-2 mechanism. The mechanisms for a positive interaction between β₂ agonists and corticosteroids are described in the discussion at the end of the section, Aerosolized Corticosteroid Agents.

Systemic side effects with aerosol administration

The rationale for the introduction of inhaled aerosol steroids was to eliminate or reduce the side effects seen with systemic therapy. Although aerosol steroids are administered in low doses because of their high topical activity, local side effects may occur, and certain systemic side effects, listed in Box 11-4, are also a concern. Some side effects may occur with transfer from oral therapy to the inhaled route. Three systemic effects of concern with inhaled steroids are HPA suppression, loss of bone density, and growth restriction in children. Possible systemic side effects with inhaled steroids are the following:

It is logical that the risks of steroid-induced adverse effects are lower with the relatively low doses of inhaled steroids compared with systemic administration. However, the threshold doses by inhalation causing adrenal suppression or other effects are unknown. These effects generally are rare with doses of 800 μg/day or less in adults and 400 μg/day or less in children. Absorption of inhaled steroid leads to systemic bioavailability, from both the swallowed portion and the inhaled portion reaching the lung. Table 11-3 summarizes data on the bioavailability of four agents. When administered orally, bioavailability ranges from less than 1% to more than 20% of the total dose; this is due to the high first-pass metabolism of the swallowed drug. In contrast, all of the inhaled dose reaching the lung is absorbed and enters the systemic circulation, where it is ultimately metabolized in the liver or extrapulmonary tissues.¹¹ The efficiency of the delivery device in depositing drug in the lungs determines the amount of drug entering the systemic circulation from the airway. Thorsson and colleagues³⁸ reported that an MDI of budesonide delivered 18% of the dose to the lungs, whereas a DPI preparation (Turbuhaler) delivered nearly twice as much (32%). Leach and colleagues³⁹ found that HFA formulations gave more than CFC formulations, with 53% of HFA beclomethasone deposited in the lung.

The higher deposition is related to the particle size distribution of the device. HFA inhalers give a much better particle size distribution than CFC devices. Unless lower doses are used with HFA devices and DPIs, greater systemic drug levels result compared with those produced with an equal dose from MDIs. Total bioavailability—and the amount of drug that can cause systemic side effects such as HPA suppression—is a function of the swallowed amount, with its bioavailability, and the inhaled amount, all of which is absorbed into the circulation. Many HFA corticosteroid doses are lower than CFC corticosteroid doses. Use of a reservoir device and mouth rinsing can minimize the oropharyngeal loss and amount of swallowed drug contributing to systemic bioavailability and potential side effects. It is necessary to adjust doses on the basis of the efficiency of the delivery system and the amount reaching the airway.

Topical (local) side effects with aerosol administration

Two of the most common side effects caused by topical application of inhaled steroids in the respiratory tract are oropharyngeal candidiasis (oral thrush) and dysphonia. Several other complications and precautions with the inhaled route are summarized below.

Use in asthma

The 2009 Global Initiative for Asthma (GINA)⁴ and the 2007 National Asthma Education and Prevention Program Expert Panel Report 3 (NAEPP EPR-3), Guidelines for the Diagnosis and Management of Asthma,¹ identify corticosteroids as long-term control agents rather than quick-relief agents. Corticosteroids traditionally have been used in asthma by the oral route for maintenance therapy of severe asthma, by the oral or intravenous route for treatment of status asthmaticus, and by inhalation for maintenance of asthma control. However, increased emphasis on asthma as a disease of inflammation leading to bronchial hyperresponsiveness has shifted the use of inhaled aerosol steroids from second-line or third-line therapy to first-line, primary therapy. The use of corticosteroids can control asthma and improve asthma symptoms by reducing exacerbations and improving lung function.¹

The principles of corticosteroid use in asthma, based on the above-mentioned guidelines, are summarized as follows:

Use in chronic obstructive pulmonary disease

The use of steroids in COPD is recognized as having potential action in relieving symptoms and exacerbations, but steroid use has little to no effect on FEV₁. The use of corticosteroids is described in the 2004 ATS guidelines² and in the 2009 GOLD guidelines.³ A review and update on COPD have been provided by Fabbri and colleagues.⁴⁷

COPD is characterized by a different pattern of inflammatory cells than is seen in asthma.^48,49 Eosinophils predominate in asthma, whereas neutrophils predominate in COPD. Oral and inhaled corticosteroids do not influence the inflammatory changes driven by neutrophils.^26,48,49

Available studies show that corticosteroid use in COPD reduces exacerbations, symptoms, and mortality⁵⁰ but has little effect on pulmonary function results.^51–54 Other studies have found that inhaled corticosteroids may slow the decline of FEV₁.^53,55

In acute exacerbations of COPD, oral or parenteral steroids are often given. Short-term corticosteroid therapy has shown benefit in hospitalized patients.^3,4 Maltais and associates⁵⁶ found that 2 mg of liquid, nebulized budesonide improved FEV₁ compared with placebo and had similar results to 30 mg of oral prednisolone. Use of inhaled corticosteroids is much safer than oral steroid use. Patients with stable COPD should not be given systemic corticosteroids.²