Adverse Effects

ADVERSE EFFECTS

General Considerations

Short-term glucocorticoid therapy of life-threatening diseases, such as status asthmaticus, provides dramatic improvement with few complications. However, when administered in pharmacological doses for long periods, steroids generally produce serious toxic effects that are extensions of their pharmacological actions. No route or preparation is free from the diverse side effects (Table 60.2), although individuals receiving comparable doses of glucocorticoids exhibit variations in side effects.

Glucocorticoids are cautiously employed in various disease states, such as rheumatoid arthritis, although they still should be regarded as adjunctive rather than primary treatment in the overall management scheme. The toxic effects of steroids are severe enough that a number of factors must be considered when their pro-longed use is contemplated.

The first point is that treatment with steroids is gen-erally palliative rather than curative, and only in a very few diseases, such as leukemia and nephrotic syndrome, do corticosteroids alter prognosis. One must also con-sider which is worse, the disease to be treated or possi-ble induced hypercortisolism. The patient’s age can be an important factor, since such adverse effects as hyper-tension are more apt to occur in old and infirm individ-uals, especially in those with underlying cardiovascular disease. Glucocorticoids should be used with caution during pregnancy. If steroids are to be employed, pred-nisone or prednisolone should be used, since they cross the placenta poorly.

Once steroid therapy is decided upon, the lowest possible dose that can provide the desired therapeutic effect should be employed. Relationships of dosage, du-ration, and host responses are essential elements in de-termining adverse effects. Increasing attention is being given to the use of lower doses of glucocorticoids in combination with other drugs that can have a synergis-tic effect on a given disease. Moreover, the lowered dose levels of steroid will minimize the side effects.

Osteoporosis

The most damaging and therapeutically limiting ad-verse effect of long-term glucocorticoid therapy is im-pairment of bone formation. This effect is associated with a decrease in serum levels of osteocalcin, a marker of osteoblastic function. In fact, glucocorticoid adminis-tration is the most common cause of drug-induced osteo-porosis. Most patients receiving chronic steroid therapy develop osteoporosis, particularly during the first year of therapy, and more than 50% will have a bone frac-ture. Trabecular bone is particularly affected.

Systemic glucocorticoid therapy increases the prob-ability of osteoporosis even with dosages sufficiently low so as not to affect the hypothalamic–pituitary– adrenal axis. By enhancing bone resorption and de-creasing bone formation, glucocorticoids decrease bone mass and increase the risk of fractures. The overall ef-fects appear to be due to direct actions of glucocorti-coids on osteoblasts and to indirect effects, such as im-paired Ca⁺⁺ absorption and a compensatory increase in parathyroid hormone secretion. Inhibition of bone growth is a well-known side effect of long-term systemic glucocorticoid therapy in children with bronchial asthma, even in those receiving alternate-day therapy. Glucocorticoids can also augment bone loss, decreasing testosterone levels in men and estrogen levels in women by direct effects on the gonads and inhibition of go-nadotropin release. Thus, patients taking glucocorti-coids can also develop hypogonadism. It is recom-mended that all patients who receive long-term glucocorticoid treatment should have measurements of bone density, gonadal steroids, vitamin D, and 24-hour urinary Ca⁺⁺ . Deficiencies in either testosterone or estradiol increase bone loss and should be corrected if possible. Bisphosphonates (etidronate, alendronate, or risedronate) and calcitonin, which inhibit bone resorp-tion, have become increasingly popular for treating os-teoporosis.

The Infectious Process

Steroids can alter host–parasite interactions, suppress fever, decrease inflammation, and change the usual character of the symptoms produced by most infectious organisms. There is a heightened susceptibility to seri-ous bacterial, viral, and fungal infections. Local infec-tions may reactivate and spread, and infections ac-quired during the course of therapy may become more severe and even more difficult to recognize. By interfer-ing with fibroblast proliferation and collagen synthesis, glucocorticoids cause dehiscence of surgical incisions, increase risk of wound infection, and delay healing of open wounds. This untoward effect of steroids may make it mandatory to administer antibiotics with the steroids, especially when there is a history of a chronic infectious process (e.g., tuberculosis). On the other hand, individuals with normal defenses who are treated with low to moderate doses of glucocorticoids are not at great risk of infection. While the incidence of infections has probably decreased with the increased use of in-haled steroids and combination therapy, inhaled steroids carry an increase in the incidence of oral can-didiasis that can be reduced by using proper doses. Nevertheless, glucocorticoids are used to treat herpes zoster, bacterial meningitis, and skin infections.

Effects on Gastric Mucosa

Steroid administration was once thought to lead to the formation of peptic ulcers, with hemorrhage or perfora-tion or reactivation of a healed ulcer. It is now realized that this effect is principally observed in patients who have received concomitant nonsteroidal antiinflamma-tory treatment. Since there is a minimal increase in the incidence of ulcers in patients receiving glucocorticoid treatment alone, prophylactic antiulcer regimens are usually not necessary.

Hyperglycemic Action

In about one-fourth to one-third of the patients receiv-ing prolonged steroid therapy, the hyperglycemic effects of glucocorticoids lead to decreased glucose tolerance, decreased responsiveness to insulin, and even glyco-suria. Ketoacidosis occurs very rarely. Pharmacological concentrations of steroids may precipitate frank dia-betes in individuals who cannot produce the necessary additional insulin. Mild hyperglycemia can often be managed with oral hypoglycemic agents. The effects of glucocorticoids on hyperglycemia are usually reversed within 48 hours following discontinuation of steroid therapy. If glucocorticoid therapy is continued for an extended period, the alterations of glucose metabolism and the resulting hyperinsulinemia may lead to en-hanced cardiovascular risk.

Ophthalmic Effects

Glucocorticoids induce cataract formation, particularly in patients with rheumatoid arthritis. An increase in intraoc-ular pressure related to a decreased outflow of aqueous humor is also a frequent side effect of periocular, topical, or systemic administration. Induction of ocular hyperten-sion, which occurs in about 35% of the general population after glucocorticoid administration, depends on the spe-cific drug, the dose, the frequency of administration, and the glucocorticoid responsiveness of the patient.

Central Nervous System Effects

Treatment with steroids may initially evoke euphoria. This reaction can be a consequence of the salutary ef-fects of the steroids on the inflammatory process or a di-rect effect on the psyche. The expression of the unpre-dictable and often profound effects exerted by steroids on mental processes generally reflects the personality of the individual. Psychiatric side effects induced by gluco-corticoids may include mania, depression, or mood dis-turbances. Restlessness and early-morning insomnia may be forerunners of severe psychotic reactions. In such situations, cessation of treatment might be consid-ered, especially in patients with a history of personality disorders. In addition, patients may become psychically dependent on steroids as a result of their euphoric ef-fect, and withdrawal of the treatment may precipitate an emotional crisis, with suicide or psychosis as a conse-quence. Patients with Cushing’s syndrome may also ex-hibit mood changes, which are reversed by effective treatment of the hypercortisolism.

The hippocampus is a principal neural target for glu-cocorticoids. It contains high concentrations of gluco-corticoid and mineralocorticoid receptors and has marked sensitivity to these hormones.

Fluid and Electrolyte Disturbances

 The normal subject may retain sodium and water during steroid therapy, although the synthetic steroid analogues represent a lesser risk in this regard. Pred-nisolone produces some edema in doses greater than 30 mg; triamcinolone and dexamethasone are much less li-able to elicit this effect. Glucocorticoids may also pro-duce an increase in potassium excretion. Muscle weak-ness and wasting of skeletal muscle mass frequently accompany this potassium-depleting action. The expan-sion of the extracellular fluid volume produced by steroids is secondary to sodium and water retention. However, the presence of specific steroid receptors in vascular smooth muscle suggests that glucocorticoids are also more directly involved in the regulation of blood pressure. The major adverse effects of glucocorti-coids on the cardiovascular system include dyslipidemia and hypertension, which may predispose patients to coronary artery disease. A separate entity, steroid my-opathy, is also improved by decreasing steroid dosage.

Pseudorheumatism

In certain patients, whose large dosages of cortico-steroids for rheumatoid arthritis are gradually dimin-ished, new symptoms develop that may be mistaken for a flare-up of the joint disease. These can include emo-tional lability, fever, muscle aches, and general fatigue. It is tempting to increase the dosage of steroid in this sit-uation, but continued maintenance at the lower dosage with a subsequent gradual decrease in the dose usually improves symptoms.

Additional Effects

Other side effects include acne, striae, truncal obesity, deposition of fat in the cheeks (moon face) and upper part of the back (buffalo hump), and dysmenorrhea. Topical administration may produce local skin atrophy. In patients with AIDS who are treated with glucocorti-coids, Kaposi’s sarcoma becomes activated or pro-gresses more rapidly.

Iatrogenic Adrenal Insufficiency

In addition to the dangers associated with long-term use of corticosteroids in supraphysiological concentrations, withdrawal of steroid therapy presents problems. The suppression of the hypothalamic–pituitary axis ob-served with modest doses and short courses of gluco-corticoid therapy is usually readily reversible. However, steroid therapy with modest to high doses for 2 weeks or longer will depress hypothalamic and pituitary activ-ity and result in a decrease in endogenous adrenal steroid secretion and eventual adrenal atrophy. These patients have a limited ability to respond to stress and an enhanced probability that shock will develop. Long-acting steroids, such as dexamethasone and betametha-sone, suppress the hypothalamic–pituitary axis more

than do other steroids. The functional state of the hypo-thalamic–pituitary axis can be evaluated by tests involv-ing basal plasma cortisol determinations, low and high doses of cosyntropin (peptide fragment of corti-cotrophin), insulin hypoglycemia, metyrapone, and corticotrophin-releasing hormone.

Glucocorticoids are not withdrawn abruptly but are tapered. The doses are altered so that the condition being treated will not flare up and recovery of the hypothalamic–pituitary axis will be facilitated. Tapering the dose may reduce the potential for the development of Addison-like symptoms associated with steroid with-drawal. Alternate-day therapy will relieve the clinical manifestations of the inflammatory diseases while allow-ing a day for reactivation of endogenous corticosteroid output, thereby causing less severe and less sustained hypothalamic–pituitary suppression. This is feasible with doses of shorter-acting corticosteroids, such as pred-nisolone. The usual daily dose is doubled and is given in the early morning to simulate the natural circadian vari-ation that occurs in endogenous corticosteroid secretion. The benefits of alternate-day therapy are seen only when steroids are used for a long period and are partic-ularly useful for tapering the dose of glucocorticoid.

Although not always predictable, the degree to which a given corticosteroid will suppress pituitary activity is re-lated to the route of administration, the size of the dose, and the length of treatment. The parenteral route causes the greatest suppression, followed by the oral route, and finally topical application. Hypothalamic–pituitary sup-pression also may result if large doses of a steroid aero-sol spray are used to treat bronchial asthma. Patients given high concentrations of steroids for long periods and subsequently exposed to undue stress (e.g., severe infection, surgery) face the danger of adrenal crisis. These patients must be given supplemental steroids to compensate for their lack of adrenal reserve and to sus-tain them during the crisis.

Acute adrenal insufficiency will, of course, occur from an abrupt cessation of steroid therapy. The causa-tion of fever, myalgia, arthralgia, and malaise may be difficult to distinguish from reactivation of rheumatic disease. Steroid treatment should be reduced gradually over several months to avoid this potentially serious problem. Also, continued suppression may be avoided by administering daily physiological replacement doses (5 mg prednisone) until adrenal function is restored. Although tapering of dose may not facilitate recovery of the hypothalamic–pituitary–adrenal axis, it may re-duce the possibility of adrenal insufficiency. This is im-portant, since severe hypotension caused by adrenal in-sufficiency may evoke a medical emergency. Adrenal insufficiency should always be considered in patients who are being withdrawn from prolonged glucocorti-coid therapy unless metyrapone or insulin hypo-glycemia tests are performed to exclude this possibility.

An additional problem associated with glucocorti-coid therapy is that certain side effects can be caused by the diseases for which glucocorticoids are adminis-tered. Thus, osteoporosis can be a sequela of rheuma-toid arthritis, and the physician is left to determine whether the untoward effect is iatrogenic or is merely a sign of the disease being treated. In addition to these problems, the physician must also be aware of the pa-tient’s natural reluctance to reduce the dose of steroid because of its salutary effects, both on the inflamma-tory process and on the psyche. Thus, the problems as-sociated with withdrawal from long-term steroid ther-apy in rheumatoid arthritis are additional reasons steroid treatment should be initiated only after rest, physiotherapy, and nonsteroidal antiinflammatory drugs or after methotrexate, gold, and D-penicillamine have been used.