Glucocorticoids in nonendocrine disorders

The glucocorticoid drugs (eg, cortisone, prednisone), also known as corticosteroids, are nearly identical to the glucose-regulating steroids produced by the adrenal cortex. Accordingly, we can look on the glucocorticoids as having two kinds of effects: physiologic and pharmacologic. Physiologic effects, such as modulation of glucose metabolism, are elicited by low doses of glucocorticoids. In contrast, pharmacologic effects (eg, suppression of inflammation) require high doses.

As implied by the chapter title, glucocorticoids have both endocrine and nonendocrine applications. In low (physiologic) doses, glucocorticoids are used to treat adrenocortical insufficiency. In high (pharmacologic) doses, glucocorticoids are used to treat inflammatory disorders (eg, asthma, rheumatoid arthritis) and certain cancers and to suppress immune responses in organ transplant recipients. The endocrine applications of the glucocorticoids are discussed in Chapter 60. Nonendocrine uses are discussed here.

Toxicity of the glucocorticoids can be severe and is determined by the pattern of drug use. Glucocorticoids are devoid of toxicity when used in physiologic doses. However, when taken in pharmacologic doses, especially for extended periods, glucocorticoids can cause an array of serious adverse effects.

All of the glucocorticoid drugs can produce the same spectrum of therapeutic effects. Differences among individual agents pertain to time course and side effects. Because the similarities among these drugs are much more striking than the differences, we will not focus on a prototypic agent. Instead, we will discuss the glucocorticoids as a group.

Review of glucocorticoid physiology

TABLE 72–1

Systemic Glucocorticoids: Half-Lives, Relative Potencies, and Equivalent Doses

Drug	Biologic Half-Life (hr)	Relative Mineralocorticoid Potency*	Relative Glucocorticoid (Anti-inflammatory) Potency^†	Equivalent Anti-inflammatory Dose (mg)^‡
Short Acting
Cortisone	8–12	2	0.8	25
Hydrocortisone	8–12	2	1	20
Intermediate Acting
Prednisone	18–36	1	4	5
Prednisolone	18–36	1	4	5
Methylprednisolone	18–36	0	5	4
Triamcinolone	18–36	0	5	4
Long Acting
Betamethasone	36–54	0	20–30	0.75
Dexamethasone	36–54	0	20–30	0.75

^*Relative mineralocorticoid activity (sodium and water retention; potassium depletion): 0 = very low, 1 = moderate, 2 = high.

^†Glucocorticoid potency values are relative to the potency of hydrocortisone.

^‡Approximate oral or intravenous dose needed to produce equivalent anti-inflammatory effects.

Respiratory system effects in neonates.

During labor and delivery, the adrenals of the full-term infant release a burst of glucocorticoids, which act to hasten maturation of the lungs. In the preterm infant, production of glucocorticoids is low, resulting in a high incidence of respiratory distress syndrome.

Control of synthesis and secretion

Synthesis and release of glucocorticoids are regulated by a negative feedback loop. The principal components of the loop are the hypothalamus, anterior pituitary, and adrenal cortex (Fig. 72–1). The loop is turned on when stress or some other stimulus from the central nervous system acts on the hypothalamus to cause release of corticotropin-releasing hormone (CRH). CRH then stimulates the pituitary to release adrenocorticotropic hormone (ACTH), which in turn acts on the adrenal cortex to promote synthesis and release of cortisol (the principal endogenous glucocorticoid). Cortisol has two basic effects: first, it stimulates physiologic responses; second, it acts on the hypothalamus and pituitary to suppress further release of CRH and ACTH. By inhibiting release of CRH and ACTH, cortisol suppresses its own production. As a result, this negative feedback loop keeps glucocorticoid levels within an appropriate range. When glucocorticoids are administered chronically in large doses, the feedback loop remains continuously suppressed. As discussed later, persistent suppression can be dangerous.

Figure 72–1 Feedback regulation of glucocorticoid synthesis and secretion.
(ACTH = adrenocorticotropic hormone, CNS = central nervous system, CRH = corticotropin-releasing hormone.)

Pharmacology of the glucocorticoids

Molecular mechanism of action

Mechanistically, glucocorticoids differ from most drugs in two ways: (1) glucocorticoid receptors are located inside the cell, rather than on the cell surface; and (2) glucocorticoids modulate the production of regulatory proteins, rather than the activity of signaling pathways.

Here’s how they do it. First, glucocorticoids penetrate the cell membrane, and then bind with receptors in the cytoplasm, thereby converting the receptor from an inactive form to an active form. Next, the receptor-steroid complex migrates to the cell nucleus, where it binds to chromatin in DNA, thereby altering the activity of target genes. In most cases, activity of the target gene is increased, causing increased transcription of messenger RNA molecules that code for specific regulatory proteins. However, in some cases, activity of the target gene is suppressed, and hence synthesis of certain regulatory proteins declines.

Pharmacologic effects

When administered in the high doses employed to treat nonendocrine disorders, glucocorticoids produce anti-inflammatory and immunosuppressive effects—effects not seen at physiologic doses. Of course, these high doses also produce the physiologic effects seen at low doses.

Effects on metabolism and electrolytes

The effects of high-dose therapy on metabolism and electrolytes are like those seen with physiologic doses—but are more intense. Hence, with high doses, glucose levels rise, protein synthesis is suppressed, and fat deposits are mobilized. As noted, most glucocorticoids have very little mineralocorticoid activity. Accordingly, these drugs do not usually induce significant sodium retention or potassium loss. However, these effects do occur in some patients and can be hazardous. In all patients, high-dose therapy can inhibit intestinal absorption of calcium, an effect not seen at physiologic doses.

Anti-inflammatory and immunosuppressant effects

The major clinical applications of the glucocorticoids stem from their ability to suppress immune responses and inflammation. Effects on the immune system and inflammation are interrelated, and hence we will consider them together.

Before discussing the actions of glucocorticoids, we need to review the process of inflammation. Characteristic symptoms of inflammation are pain, swelling, redness, and warmth. These are initiated by chemical mediators (prostaglandins, histamine, leukotrienes) and are amplified by the actions of lymphocytes and phagocytic cells (neutrophils and macrophages). Prostaglandins and histamine promote several symptoms of inflammation—swelling, redness, and warmth—by causing vasodilation and increasing capillary permeability. Prostaglandins and histamine contribute to pain: histamine stimulates pain receptors directly; prostaglandins sensitize pain receptors to stimulation by histamine and other mediators. Neutrophils and macrophages heighten inflammation by releasing lysosomal enzymes, which cause tissue injury. Lymphocytes, which are important elements of the immune system, intensify inflammation by (1) causing direct cell injury and (2) promoting formation of antibodies that help perpetuate the inflammatory response.

Glucocorticoids act through several mechanisms to interrupt the inflammatory processes. These drugs can inhibit synthesis of chemical mediators (prostaglandins, leukotrienes, histamine) and can thereby reduce swelling, warmth, redness, and pain. In addition, they suppress infiltration of phagocytes. Hence, damage from lysosomal enzymes is averted. Lastly, glucocorticoids suppress proliferation of lymphocytes, and thereby reduce the immune component of inflammation.

It is important to appreciate that the mechanisms by which glucocorticoids suppress inflammation are more diverse than the mechanisms by which nonsteroidal anti-inflammatory drugs (NSAIDs) act. As discussed in Chapter 71, NSAIDs suppress inflammation primarily by inhibiting prostaglandin production. The glucocorticoids share this mechanism and act in other ways too. Because they act by multiple mechanisms, glucocorticoids have much greater anti-inflammatory effects than do NSAIDs.

Pharmacokinetics

Absorption.

The rate of glucocorticoid absorption depends on the route of administration and the specific glucocorticoid. With oral administration, absorption of all glucocorticoids is rapid and nearly complete. Following IM injection, absorption is rapid with two types of glucocorticoid esters (sodium phosphates and sodium succinates) and relatively slow with other derivatives (eg, acetates, acetonides). Absorption from local sites of injection (eg, intra-articular, intrasynovial) is slower than from IM sites.

Duration of action.

Duration depends on dosage, route, and drug solubility. For glucocorticoids administered orally or IV, duration is determined largely by biologic half-life (see Table 72–1). With IM administration, duration is a function of water solubility: Highly soluble preparations have a shorter duration than less soluble preparations. For locally administered glucocorticoids, duration is determined by solubility and by the specific site of administration.

Metabolism and excretion.

Glucocorticoids are metabolized primarily by the liver. As a rule, the resulting metabolites are inactive. Excretion of metabolites is renal.

Therapeutic uses in nonendocrine disorders

Glucocorticoids are used to treat endocrine disorders and nonendocrine disorders. Endocrine disorders (eg, Addison’s disease) can be managed with low-dose therapy and are considered in Chapter 60. Nonendocrine applications, which require much higher doses, are discussed here. Because prolonged, high-dose therapy can produce serious adverse effects, the potential benefits of treatment must be weighed carefully against the very real risks.

Rheumatoid arthritis.

Glucocorticoids are indicated for adjunctive treatment of acute exacerbations of rheumatoid arthritis. These drugs can reduce inflammation and pain, but do not alter the course of the disease. Because of the risk of serious complications, prolonged systemic use should be avoided.

When arthritis is limited to just a few joints, intra-articular injections should be employed. Local injections can be highly effective and cause less toxicity than systemic therapy. Frequently, reductions in pain and inflammation may be so dramatic as to prompt vigorous use of joints that were previously immobile. Since excessive use of diseased joints can cause injury, patients should be warned against overactivity, even though symptoms have eased.

The use of glucocorticoids in rheumatoid arthritis is discussed further in Chapter 73.

Systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic disease similar in many ways to rheumatoid arthritis. However, in SLE, inflammation is not limited to joints. Rather, it occurs throughout the body. Symptoms frequently include pleuritis, pericarditis, and nephritis. A severe episode can be fatal. Fortunately, manifestations of SLE can usually be controlled with prompt and aggressive glucocorticoid therapy.

Inflammatory bowel disease.

Glucocorticoids are used to treat severe cases of ulcerative colitis and Crohn’s disease, the two most common forms of inflammatory bowel disease. Administration may be oral or intravenous. Glucocorticoid therapy of these disorders is considered further in Chapter 80.

Miscellaneous inflammatory disorders.

Glucocorticoids are useful in a variety of inflammatory disorders in addition to those discussed above. Conditions that respond include bursitis, tendinitis, synovitis, osteoarthritis, gouty arthritis, and inflammatory disorders of the eye.

Allergic conditions.

Glucocorticoids can control symptoms of allergic reactions. Responsive conditions include allergic rhinitis (see Chapter 77), bee stings, and drug-induced allergies. Because glucocorticoid responses are delayed, these drugs have little value as acute therapy for severe allergic reactions (eg, anaphylaxis). For life-threatening allergic reactions, epinephrine is the treatment of choice.