Oral Corticosteroids
By Julie Goslee, Pharm.D., and Victoria Robinson, Pharm.D. Candidate

ACPE Program 207-000-97-005-H01
May 1997 (Expires May 1, 2000)

Educational Objectives:
After reading this article, the pharmacist should be able to:
1. Understand the pharmacologic profile of oral corticosteroids
2. Describe the therapeutic role of oral corticosteroids
3. Understand adverse effects associated with oral corticosteroid use
4. Recognize potential drug-drug interations with oral corticosteroids; and
5. Describe the pharmacist's role in managing the patient taking oral corticosteroids.

INTRODUCTION
Oral corticosteroids have a variety of therapeutic and diagnostic applications including adrenal insufficiency, rheumatic and collagen diseases, allergic conditions, organ transplantation, neoplastic diseases, cerebral edema, as well as for diseases affecting the eyes, lungs, gastrointestinal tract, and liver. Thus the focus of this article will encompass the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, as well as patient counseling tips of these agents.

ORAL CORTICOSTEROIDS
Corticosteroids are hormones secreted by the adrenal cortex or are synthetic analogs of these hormones. They are typically classified as glucocorticoids or mineralocorticoids. They are further classified as short-acting, intermediate, or long-acting based on their duration of action (Table 1). Corticosteroids may be administered orally, intravenously, intramuscularly, topically, intra-articularly, intrasynovially, or via inhalation. This article focuses on the orally administered glucocorticoids.

Table 1. Oral Glucococorticoid Preparations

DRUG	TRADE NAME	ORAL DOSAGE STRENGTHS
SHORT-ACTING GLUCOCORTICOIDS
Cortisone Acetate	Cortone	5, 10, 25 mg tabs
Hydrocortisone	Cortison, Cortef Hydrocortone	5, 10, 25 mg tabs
INTERMEDIATE-ACTING GLUCOCORTICOIDS
Methylprednisolone	Medrol	2, 4, 8, 16, 24, 32, mg tabs
Prednisolone	Delta-Cortef, Prelone	5 mg tabs; 15 mg/5ml syrup
Prednisone	Deltasone, Orasone, liquidf Pred	1, 2,5, 5, 10, 25, 50, mg tabs; 5mg/5ml susp, syrup
Triamcinalone	Kenacfort, Aristacort	1, 2, 4, 8, mg tabs; 2, 4 mg/5ml syrup
LONG-ACTING GLUCOCORTICOIDS
Betamethasone	Celestone	0.6 mg tabs; 0.6 mg/5ml syrup
Dexamethasone	Decadron	0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6 mg tabs; .05 mg/5ml solution
Mineralocorticoid	Fludrocortisone, Florinef	0.1 mg tab

PHARMACOLOGY
The pharmacology of the oral corticosteroids is complex and not well understood, but it is postulated that the effects of these drugs result from modification of enzyme activity rather than from direct actions by the drugs. The effects of the corticosteroids are numerous and widespread. These drugs promote gluconeogenesis, protein catabolism, and redistribution of fat from peripheral to central areas of the body; influence electrolyte and water balance by enhancing the reabsorption of sodium from the renal tubules and increasing the urinary excretion of potassium and hydrogen ions; and affect the functions of the cardiovascular system, the kidneys, muscles, nervous system, and other organs and tissues. In addition, the oral corticosteroids enhance the body's ability to resist many types of harmful stimuli and environmental changes.

PHARMACOKINETICS
The corticosteroids are well absorbed from the gastrointestinal tract following oral administration and quickly distribute to muscles, liver, skin, intestines, and kidneys. In addition, oral corticosteroids cross the placenta and may be secreted in breast milk. Plasma protein binding of corticosteroids ranges from 61% to 95%. Because only unbound drug is pharmacologically active, patients with low serum albumin concentrations may be more susceptible to effects of corticosteroids than patients with normal serum albumin concentrations. These drugs are metabolized in most tissues, primarily in the liver, to biologically inactive metabolites that are excreted primarily by the kidneys. Although the elimination half-lives of these agents are relatively short (1-5 hours), the biologic half-lives are much longer, ranging from 8 to 60 hours.

INDICATIONS FOR USE
In physiologic dosages, corticosteroids are used to replace deficient endogenous hormones. In larger (pharmacologic) dosages, the drugs have both therapeutic and diagnostic applications based upon their ability to suppress the release of adrenocorticotropic hormone (ACTH) from the pituitary gland and the subsequent secretion of endogenous corticosteroids from the adrenal cortex.

Adrenocortical Insufficiency: Oral corticosteroids are administered in physiologic dosages to replace deficient endogenous hormones in patients with adrenocortical insufficiency. Because production of both glucocorticoids and mineralocorticoids is deficient in these patients, either hydrocortisone or cortisone (in conjunction with liberal salt intake) is the oral corticosteroid of choice for replacement therapy in dosages of 10-30 mg daily and 10-50 mg daily in divided doses, respectively. Fludrocortisone, a potent mineralocorticoid may also be required in some patients.

Rheumatoid Disorders and Collagen Diseases: In rheumatoid arthritis, the criterion for initiating oral corticosteroid therapy is progressive disease with consequent disability, despite intensive treatment with rest, physical therapy, aspirin, NSAIDS, gold, and other agents. The decision to initiate oral corticosteroid therapy is weighty: once started, corticosteroid therapy may have to be continued for many years, increasing the risk of serious adverse effects. The initial dose should be low and gradually increased slowly until the desired degree of control is obtained. The usual initial dose is 10 mg of prednisone (or equivalent) per day in divided doses. Higher dosages may be administered during the acute phase of the disease and should quickly be reduced after the crisis is past. Manifestations of systemic lupus erythematosus and other collagen diseases should be suppressed with oral corticosteroid therapy in doses large enough to produce a prompt effect. Treatment usually consists of a 1 mg/kg daily dose of prednisone or equivalent. Doses may be increased in 20 mg increments daily if necessary until a favorable response occurs. Oral corticosteroids do not alter the progression of these diseases, but are indicated for short-term management of acute exacerbations of these inflammatory conditions.

Allergic Conditions: Acute manifestations of allergic disease such as hay fever, serum sickness, urticaria, bee stings, contact dermatitis, drug hypersensitivity, and angioedema may be suppressed by adequate doses of oral corticosteroids given as supplement to primary therapy. In life-threatening situations, corticosteroids may need to be administered intravenously. These drugs should generally be reserved for acute conditions and severe exacerbations, and should be tapered once the acute crisis is over.

Respiratory Diseases: Oral corticosteroids may be used for symptomatic relief of acute manifestations of respiratory diseases such as asthma and chronic obstructive pulmonary disease. These agents reduce the number and activity of inflammatory cells in the airway mucosa and may directly reduce the release of particular mediators (e.g., leukotrienes). Acute exacerbations of asthma or COPD are often treated with brief courses of oral corticosteroids. Upon restoration of adequate responses to other medications such as inhaled beta 2-adrenergic agonist and/or oral theophylline, the corticosteroid is usually withdrawn.

Organ Transplantation: In organ transplantation, high doses of prednisone (50 to 100 mg) are given at the time of the transplant surgery, usually in conjunction with immunosuppressive agents. Smaller maintenance doses (10 to 20 mg per day) are continued indefinitely, and the dosage is increased if rejection is threatened.

Malignancies: High doses of oral corticosteroids are used either alone or in combination in various chemotherapeutic regimens in the palliative treatment of neoplastic diseases of the lymphatic system (leukemias and lymphomas) because of their antilymphocytic effects. Prednisone is commonly used in combination with an alkylating agent such as cyclophosphamide, an antimetabolite, and a vinca alkaloid.

Gastrointestinal Diseases: Patients experiencing acute exacerbations of inflammatory bowel disease (ulcerative colitis and Crohn's disease), regional enteritis, and celiac disease may benefit from a moderate to high dosage course of oral corticosteroid therapy. Corticosteroids are useful as short-term palliative therapy and are rarely indicated for maintenance therapy in chronic gastrointestinal diseases since they do not prevent relapses and may produce serious adverse effects with long-term administration.

Other uses of oral corticosteroids include hypercalcemia, dermatologic diseases, shock, multiple sclerosis, and renal disease.

ADVERSE EFFECTS
Short-term use of oral corticosteroids is usually unlikely to produce adverse effects. Doses equivalent to several hundred times the daily synthesis of cortisol (e.g. prednisone 100 mg ) can be given for a few days with insignificant toxicity. With chronic therapy of oral corticosteroids, the incidence of serious adverse effects increases (Table 2).

Table 2: Adverse Effects of Oral Corticosteroids

Hyperglucemia Increased risk of infectionH Hypokalemia Increased risk of peptic ulcers Myopathy Behavior changes Cataracts/Glaucoma Growth retardation in children Adrenal supression Cushing's Disease Skin atrophy Impaired wound healing Fluid retention Weight gain Osteoporosis Hypertension

Adrenal Suppression: In pharmacologic doses, oral corticosteroids may cause decreased secretion of endogenous corticosteroids by suppressing the release of corticotropin (ACTH) from the pituitary gland. The degree and duration of adrenal suppression is highly variable among patients and depends on the dose, frequency and time of administration and the duration of oral corticosteroid use.

Increased Susceptibility to Infection: Oral corticosteroids are immunosuppressive agents and may increase susceptibility to and mask symptoms of infection. The increased susceptibility to infection is generally not considered to be specific for any particular bacterial or fungal pathogen. If an infection develops in a patient taking oral corticosteroid therapy, the steroid dose may be continued and even increased, and the most effective antimicrobial treatment should be administered.

Musculoskeletal Effects: Protein cata-bolism, muscle wasting, muscle pain or weakness and poor wound healing are adverse effects associated with these drugs. In addition, protein matrix of the bone may atrophy resulting in osteoporosis, vertebral compression fractures, or fractures of the long bones. These adverse effects may be especially serious in postmenopausal women and geriatric or debilitated patients.

Ocular Effects: Chronic use of oral corticosteroids may result in cataracts or glaucoma.

Endocrine Effects: Prolonged use of oral corticosteroids may produce various endocrine disorders including a cushingoid state characterized by weight gain with central obesity (buffalo hump) and facial rounding (moon face); decreased glucose tolerance, hyperglycemia, glycosuria, and increased insulin or oral antidiabetic agent requirements; and hypogonadism.

Dermatologic Effects: Various adverse dermatologic effects are associated with oral corticosteroid use including acne; skin atrophy and thinning; impaired wound healing; hirsutism; easy bruising; and striae of abdomen, thighs, and axillas.

Gastrointestinal Effects: Peptic ulceration is an occasional adverse effect associated with oral corticosteroid therapy. The insidious nature of the development, reactivation, perforation, and/or hemorrhage of these ulcers makes this adverse effect of oral corticosteroids a serious therapeutic problem. Other adverse gastrointestinal effects of oral corticosteroids include nausea, vomiting, anorexia, increased appetite, weight gain, abdominal distention, pancreatitis, gastric irritation, and ulcerative esophagitis.

Nervous System Effects: Behavioral changes may occur with oral corticosteroid usage and may take various forms, including nervousness, insomnia, euphoria, mood swings, anxiety, depression, personality changes, psychoses, and even suicidal tendencies. Previous psychiatric problems do not predispose a patient to behavioral disturbances, and the absence of a history of psychiatric illness is no guarantee against the occurrence of psychosis during oral corticosteroid therapy. Other neurologic adverse effects of oral corticosteroids are headache, vertigo, and seizures.

Other adverse effects associated with chronic use of oral corticosteroids include renal calculi; polyuria; hypokalemic alkalosis; sodium retention with resultant edema; growth retardation in children; and hypertension.

DRUG INTERACTIONS
Oral corticosteroids are generally devoid of major drug-drug interactions. However, caution should be used when administering oral corticosteroids with NSAIDs such as indomethacin and ketorolac and other ulcerogenic agents because this combination may increase the risk of gastrointestinal ulceration. Signs and symptoms of gastrointestinal bleeding (dark tarry stools, bright red blood in stools, vomiting) should be monitored in patients receiving NSAIDs and oral corticosteroids. In addition, oral corticosteroids may markedly enhance the elimination of aspirin and/or salicylates resulting in subtherapeutic salicylate concentrations in some patients.

Enzyme Inducers: Barbiturates (phenobarbital, primidone), phenytoin, carbamazepine, and rifampin may reduce the serum concentration of oral corticosteroids sufficiently to impair their therapeutic effects. These drugs work be inducing hepatic microsomal enzymes and subsequently increasing the metabolism of oral corticosteroids. It may not be necessary to avoid the concomitant use of oral corticosteroids and enzyme inducing drugs, but observation for reduced oral corticosteroid response is warranted. A higher dosage of oral corticosteroid may be required.

Cholestyramine: Cholestyramine and other binding agents may inhibit the gastrointestinal absorption of oral corticosteroids and possibly reduce the therapeutic effects. Doses of oral corticosteroids and cholestyramine should be separated as much as possible to minimize their mixing in the gastrointestinal tract. Patients should be monitored for evidence of reduced oral corticosteroid response, and an increased dosage may be needed when these drugs are given concurrently.

DOSAGE AND ADMINISTRATION
Oral corticosteroids should be administered in the smallest dosage possible and should generally be used only as adjuncts to other treatments. Patients should continuously be monitored for drug effectiveness and adverse effects, and periodic attempts should be made to decrease the dosage and/or withdraw the therapy completely. Prescription refills should be limited so that periodic evaluations can be made of the patient's condition.

Types of dosages of oral corticosteroids are either physiologic or replacement (amount of glucocorticoid normally secreted by the adrenal cortex each day-approximately 20 mg of hydrocortisone) and pharmacologic (any dosage greater than a physiologic dosage). Pharmacologic dosages can be further classified into low, moderate, high, and massive.

With long-term therapy, alternate-day dosing of oral corticosteroids should be considered. This dosing strategy involves giving a single dose every other morning. The drug is administered in the morning to simulate the natural circadian rhythm of cortisol secretion, which is high in the morning and low in the evening. This regimen provides relief of symptoms while minimizing the risk of adverse effects. The most common method involves administering twice the total daily dose as a single dose every other day; this dose may gradually be decreased to maintenance levels.

Discontinuation of oral corticosteroids following long-term therapy should be very gradual to allow the suppressed HPA-axis to recover. A popular method of slow tapering of oral corticosteroids involves decreasing the steroid dosage by the equivalent of 2.5-5 mg of prednisone every three to seven days until the physiologic dosage (5 mg of prednisone) is reached. Some patients may require a slower taper.

SUMMARY
Oral corticosteroids can be safely used in several disease states; however, serious adverse effects are possible. Life-threatening side effects can be avoided through careful monitoring and with the help of a knowledgeable health care provider. Pharmacists should keep abreast of changing drug regimens and closely follow their patients who are receiving oral corticosteroid therapy.

Patient Counseling Tips

1. Take medication with food. 2. Make physician aware of any concurrent disease such as diabetes mellitus, infection, hypertension, osteoporosis, or peptic ulcer. 3. During prolonged therapy, patients should be seen regularly and monitored for gastric discomfort and electrolytic imbalances, particularly potassium. 4. Make physician aware of any potassium wasting diuretics the patient may be taking. 5. Be mindful of back pain and weight gain which may indicage osteoporosis and fluid retention, respectively.