PREDNISOLONE

A brief review of the HPA physiology may be helpful in understanding this rationale. Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH secretion.

Normally the HPA system is characterized by diurnal (circadian) rhythm. m. m. m. m. This rise in cortisol dampens ACTH production and in turn adrenocortical activity. There is a gradual fall in plasma corticoids during the day, the lowest levels occurring about midnight.

The diurnal rhythm of the HPA axis is lost in Cushing’s disease, a syndrome of adrenocortical hyperfunction characterized by obesity with centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension, latent diabetes, osteoporosis, electrolyte imbalance, etc.

The same clinical findings of hyperadrenocorticism may be noted during the longterm pharmacologic dose corticoid therapy administered in conventional daily divided doses. It would appear, then, that a disturbance in the diurnal cycle with maintenance of elevated corticoid values during the night may play a significant role in the development of undesirable corticoid effects.

Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable pharmacologic effects. During conventional pharmacologic dose corticosteroid therapy, ACTH production is inhibited with subsequent suppression of cortisol production by the adrenal cortex.

Recovery time for normal HPA activity is variable depending upon the dose and duration of treatment. During this time the patient is vulnerable to any stressful situation. Although it has been shown that there is considerably less adrenal suppression following a single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every 6 hours, there is evidence that some suppressive effect on adrenal activity may be carried over into the following day when pharmacologic doses are used.

Further, it has been shown that a single dose of certain corticosteroids will produce adrenocortical suppression for two or more days. Other corticoids, including methylprednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing adrenocortical suppression for 1 1/4 days to 1 1/2 days following a single dose) and thus are recommended for alternate-day therapy.

The following should be kept in mind when considering alternate-day therapy:

Basic principles and indications for corticosteroid therapy should apply. The benefits of alternate-day therapy should not encourage the indiscriminate use of steroids. Alternate-day therapy is a therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated.

In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with alternate-day therapy. More severe disease states usually will require daily divided high dose therapy for initial control of the disease process.

The initial suppressive dose level should be continued until satisfactory clinical response is obtained, usually four to ten days in the case of many allergic and collagen diseases. It is important to keep the period of initial suppressive dose as brief as possible particularly when subsequent use of alternate-day therapy is intended.

Once control has been established, two courses are available: (a) change to alternate-day therapy and then gradually reduce the amount of corticoid given every other day, or (b) following control of the disease process, reduce the daily dose of corticoid to the lowest effective level as rapidly as possible and then change over to an alternate-day schedule.

Theoretically, course (a) may be preferable. , patients with rheumatoid arthritis). Since these patients may already have a suppressed HPA axis, establishing them on alternate-day therapy may be difficult and not always successful. However, it is recommended that regular attempts be made to change them over.

It may be helpful to triple or even quadruple the daily maintenance dose and administer this every other day rather than just doubling the daily dose if difficulty is encountered. Once the patient is again controlled, an attempt should be made to reduce this dose to a minimum.

, dexamethasone and betamethasone). m. m. and midnight. ). In using alternate-day therapy it is important, as in all therapeutic situations, to individualize and tailor the therapy to each patient. Complete control of symptoms will not be possible in all patients.

An explanation of the benefits of alternate-day therapy will help the patient to understand and tolerate the possible flare-up in symptoms which may occur in the latter part of the off-steroid day. Other symptomatic therapy may be added or increased at this time if needed.

In the event of an acute flare-up of the disease process, it may be necessary to return to a full suppressive daily divided corticoid dose for control. Once control is again established, alternate-day therapy may be reinstituted. Although many of the undesirable features of corticosteroid therapy can be minimized by alternate-day therapy, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient with whom corticoid therapy is being considered.

If varicella develops, treatment with antiviral agents may be considered. If a prednisolone-treated patient is exposed to measles, prophylaxis with immunoglobulin may be indicated. Hepatitis B Virus Reactivation Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including prednisolone.

Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection. , prolonged) treatment with prednisolone. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy.

Fungal Infections Corticosteroids, including prednisolone, may exacerbate systemic fungal infections; therefore, avoid prednisolone use in the presence of such infections unless prednisolone is needed to control drug reactions. For patients on chronic prednisolone therapy who develop systemic fungal infections, prednisolone withdrawal or dosage reduction is recommended.

Amebiasis Corticosteroids, including prednisolone, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating prednisolone in patients who have spent time in the tropics or patients with unexplained diarrhea.

Strongyloides Infestation Corticosteroids, including prednisolone, should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Cerebral Malaria Avoid corticosteroids, including prednisolone, in patients with cerebral malaria. Kaposi’s Sarcoma Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions.

Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma. Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.

Usage in Pregnancy Since adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in pregnancy, nursing mothers or women of childbearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus.

Infants born of mothers who have received substantial doses of corticosteroids during pregnancy, should be carefully observed for signs of hypoadrenalism. Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium.

These effects are less likely to occur with synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. While on corticosteroid therapy patients should not be vaccinated against smallpox.

Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response.