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