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 antiinflammatory 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. 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.
Antiinflammatory 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, so 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), reducing swelling, warmth, redness, and pain. In addition, they suppress infiltration of phagocytes, so 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 antiinflammatory drugs (NSAIDs) act. As discussed in Chapter 55, 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 antiinflammatory 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. After intramuscular (IM) injection, absorption is rapid with two types of glucocorticoid esters (sodium phosphates and sodium succinates) and relatively slow with other derivatives (e.g., acetates, acetonides). Absorption from local sites of injection (e.g., intraarticular, intralesional) is slower than from IM sites.
Duration of Action
Duration depends on dosage, route, and drug solubility. For glucocorticoids administered orally or intravenously, duration is determined largely by biologic half-life (see Table 56.1). 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
As has been mentioned, high-dose therapy is required for management of nonendocrine conditions. For some conditions, long-term therapy is required as well. 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 for serious complications, prolonged systemic use should be avoided when possible.
When arthritis is limited to just a few joints, intraarticular injections may be advantageous. Local injections can be highly effective and cause less toxicity than systemic therapy. Frequently, reductions in pain and inflammation can be so dramatic as to prompt vigorous use of joints that were previously immobile. Because 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 57.
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 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 64.
Miscellaneous Inflammatory Disorders
Glucocorticoids are useful in a variety of inflammatory disorders in addition to those discussed previously. 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 61), bee stings, and drug-induced allergies. Because glucocorticoid responses are delayed, these drugs have little value as sole therapy for severe allergic reactions (e.g., anaphylaxis). For life-threatening allergic reactions, epinephrine is the treatment of choice.
Asthma
Glucocorticoids are the most effective antiasthma agents available. For treatment of asthma, they may be administered orally or by inhalation. Adverse effects are minimal with inhaled glucocorticoids. In contrast, oral therapy can cause serious toxicity and hence should be reserved for patients who have failed to respond to safer treatments (e.g., inhaled glucocorticoids, inhaled cromolyn sodium). The use of glucocorticoids in asthma is discussed at length in Chapter 60.
Dermatologic Disorders
Glucocorticoids are beneficial in a wide variety of skin diseases, including pemphigus, psoriasis, mycosis fungoides, seborrheic dermatitis, contact dermatitis, and exfoliative dermatitis. For mild disease, topical administration is usually adequate. For severe disorders, systemic therapy may be needed. It should be noted that topical glucocorticoids can be absorbed in amounts sufficient to produce systemic toxicity. Topical therapy is discussed further in Chapter 85.
Adverse Effects
PATIENT-CENTERED CARE ACROSS THE LIFE SPAN
Glucocorticoids
| Life Stage | Patient Care Concerns |
| Children | Long-term use of steroid medications can cause inhibition of bone growth. This may result in decreased stature. |
| Pregnant women | Glucocorticoids are classified in U.S. Food and Drug Administration Pregnancy Risk Category C or D, depending on the specific drug and formulation. Inadequate studies have been conducted in pregnant women; however, studies in animals have demonstrated both teratogenic and physiologic effects. These range from an increased incidence of cleft palate, spontaneous abortion, and low birth weight in nonprimates to impaired postnatal growth, impaired glucose-insulin homeostasis, increased blood pressure, and increased production of cortisol in response to mild stress in primates. |
| Breastfeeding women | When physiologic doses or low pharmacologic doses are used, the concentration achieved in milk is probably too low to affect the nursing infant. However, when large pharmacologic doses are employed, the amount ingested by the infant may be sufficient to cause growth delay and other adverse effects. Breastfeeding is not recommended for women taking large doses of glucocorticoids. |
| Older adults | Long-term use of glucocorticoids can cause osteoporosis, adrenal insufficient, and GI ulceration. These may affect older adults disproportionately. |
The adverse effects discussed next occur in response to pharmacologic (as opposed to physiologic) doses of glucocorticoids. The intensity of these effects increases with dosage size and treatment duration. These effects are not seen when dosage is physiologic. Furthermore, most are not seen when treatment is brief (a few days or less), even when doses are high.
Adrenal Insufficiency
Prolonged administration of pharmacologic doses of glucocorticoids can suppress production of glucocorticoids by the adrenal glands, resulting in adrenal insufficiency. The mechanism, consequences, and management of adrenal insufficiency are discussed under “Adrenal Suppression.”
Osteoporosis
Development
Osteoporosis with resultant fractures is a frequent and serious complication of prolonged systemic glucocorticoid therapy. (Although osteoporosis is likely with prolonged systemic glucocorticoid therapy, it is uncommon when glucocorticoids are inhaled or administered topically.) The ribs and vertebrae are affected most. In some patients on high-dose glucocorticoids, vertebral compression fractures occur within weeks of beginning glucocorticoid use. Patients should be observed for signs of compression fractures (back and neck pain) and for indications of fractures in other bones.
How do glucocorticoids cause bone loss? The most important mechanism is suppression of bone formation by osteoblasts. In addition, glucocorticoids accelerate bone resorption by osteoclasts. Also, these drugs reduce intestinal absorption of calcium, causing hypocalcemia. In response to hypocalcemia, release of parathyroid hormone increases, which increases mobilization of calcium from bone.
Management
Several measures can greatly reduce development of osteoporosis and subsequent fractures. Before glucocorticoid treatment, bone mineral density of the lumbar spine should be measured. This will identify patients at highest risk and provide a baseline for evaluating bone loss during treatment. When appropriate, glucocorticoids should be administered topically or by inhalation because bone loss is less with these routes than with systemic therapy.
Drugs can help reduce bone loss. All patients should receive calcium and vitamin D supplements. Sodium restriction combined with a thiazide diuretic can enhance intestinal absorption of calcium and can decrease urinary excretion of calcium. There is solid evidence that a bisphosphonate can prevent glucocorticoid-induced bone loss by inhibiting bone resorption by osteoclasts. Calcitonin [Miacalcin], which also inhibits osteoclasts, is another option. For patients with significant bone loss, teriparatide [Forteo] may be preferred because, unlike bisphosphonates and calcitonin, which only prevent bone resorption, teriparatide actively promotes new bone formation. In postmenopausal women, estrogen therapy is an effective way to reduce bone loss. However, as discussed in Chapter 48, the risks of estrogen therapy generally outweigh the benefits. The roles of calcium, vitamin D, bisphosphonates, calcitonin, teriparatide, and estrogen in the prophylaxis and treatment of osteoporosis are discussed fully in Chapter 59.
Infection
By suppressing host defenses (immune responses and phagocytic activity of neutrophils and macrophages), glucocorticoids can increase susceptibility to infection. The risk for acquiring a new infection is increased, as is the risk for reactivating a latent infection (e.g., tuberculosis). In addition, because suppression of both the immune system and neutrophils reduces inflammation and other manifestations of infection, a fulminant infection may develop without detection. Hence, glucocorticoids not only increase susceptibility to infection but also can mask the presence of an infection as it progresses. To minimize risk for infection, patients should avoid close contact with people who have a communicable disease. If a significant infection occurs, glucocorticoids should be continued only if absolutely necessary, and then only in combination with appropriate antimicrobial or antifungal therapy.
One infection—known as PCP (for Pneumocystis pneumonia)—deserves special mention. The causative organism is Pneumocystis jiroveci (formerly called Pneumocystis carinii). PCP, commonly known as an opportunistic infection in people with AIDS, also occurs with alarming frequency in people receiving high doses of glucocorticoids. Accordingly, it has been suggested that PCP prophylaxis be considered for all people taking glucocorticoids long term in high doses.
Glucose Intolerance
Because of their effects on glucose production and utilization, glucocorticoids can increase plasma glucose levels, thereby causing hyperglycemia and glycosuria. Patients with diabetes may need to increase the dosage of hypoglycemic medication. For patients with normal pancreatic function, significant elevation of blood glucose is unlikely. However, because glucocorticoids can unmask latent diabetes, even patients without a diagnosis of diabetes should undergo periodic evaluation of blood glucose levels.
Myopathy
High-dose glucocorticoid therapy can cause myopathy (muscle injury), manifesting as weakness. The proximal muscles of the arms and legs are affected most. Damage to muscle may be sufficient to prevent ambulation. If myopathy develops, glucocorticoid dosage should be reduced. Myopathy then gradually resolves over several months.
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