Clinical Review Glucocorticoids in Clinical Practice Eileen G. Holland, PharmD, and A. Thomas Taylor, PharmD Augusta and Athens, Georgia The many unique features o f glucocorticoids makes complete, patients require daily physiologic replace­ therapy with these steroids challenging. The anti-in­ ment doses; high-dose supplemental therapy may be flammatory potency, relative mineralocorticoid activity, required during a major illness or surgery. Once there plasma half-life, and route of administration of the syn­ are signs o f improvement, the dosing regimen should thetic cortisol preparations are compared. Because they be adjusted to a single morning dose, then to an alter­ produce profound anti-inflammatory and immunosup­ nate-day regimen, and, as soon as possible, the steroid pressive effects, exogenously administered glucocorti­ should be discontinued. This tapering process main­ coids are effective therapy for a variety o f diseases and tains disease suppression while minimizing toxicity; conditions. The appropriate dosing regimen is an ade­ quate dose administered for a sufficient period to pre­ however, it is often complicated by exacerbation of the cipitate an acceptable response. It is impossible to pre­ disease and withdrawal symptoms. Potential complica­ dict the regimen that will suppress the hypothalamic- tions associated with glucocorticoid therapy are numer­ pituitary-adrenocortical (HPA) axis and thereby ous, involve all organ systems, and are potentially more increase the risk o f developing adrenal insufficiency devastating than the HPA axis suppression. during periods o f stress. Until recovery o f the axis is / Pam Pract 1991; 32:512-519. For several decades glucocorticoids have been used ex­ culation (Figure 1). A hypothalamic hormone, corti­ tensively in the management o f a wide spectrum o f diseases. cotropin-releasing factor, stimulates the release of] First isolated in 1935 by Kendall and co-workers, cortisone adrenocorticotropic hormone (ACTH), or corticotropin, | was administered to a woman with severe rheumatoid which stimulates the adrenal cortex to secrete cortisol. arthritis in 1948. Although the clinical improvement was Through a negative-feedback mechanism, an increase in dramatic, certain side effects became apparent.1 During circulating cortisol results in inhibition o f corticotropin-1 subsequent years, much information concerning the bio­ releasing factor and subsequent ACTH secretion.3 In, chemistry, pharmacology, tissue effects, toxicity, and clini­ humans, glucocorticoids are synthesized in a series of1 cal use o f glucocorticoids has accumulated. The mecha­ reactions that converts cholesterol to pregnenolone, to | nisms by which glucocorticoids exert their anti­ progesterone, and finally to cortisol. inflammatory and immunosuppressive effects remain In adults, about 20 mg of cortisol is secreted daily elusive, however. This article provides information neces­ from the adrenal cortex. This secretion is considered the sary for clinicians to properly prescribe glucocorticoids. physiologic replacement amount. In children, about 12 mg/m2 is secreted daily. The normal diurnal cycle results in peak cortisol levels in the morning with a gradual Hypothalamic-Pituitary- tapering off by mid to late afternoon.1’3 During periods Adrenocortical Axis o f acute stress, the adrenal cortex can secrete up to 300 mg of cortisol per day.4-5 The hypothalamic-pituitary-adrenocortical (HPA) axis controls the amount of cortisone present in normal cir- Glucocorticoid Preparations and Submitted, revised, October 5, 1990. Routes of Administration From the University of Georgia College of Pharmacy, Athens, and Department of Several synthetic analogues o f cortisol are currently avail­ Fdmily Medicine, M edical College o f Georgia, Augusta. Requests for reprints should be able for systemic use. The anti-inflammatory potency, addressed to Eileen G. Holland, PharmD, FI 1076, Medical College of Georgia, Augusta, Georgia 30912. relative mineralocorticoid activity, and plasma half-life ot © 1991 Appleton & Lange ISSN 0094-3509 512 The Journal of Family Practice, Vol. 32, No. 5, 1991 Glucocorticoids Holland and Taylor Table 1. Comparison of Glucocorticoid Preparations Equivalent Anti­ Sodium- Plasma inflammatory Retaining Half-life Dose (mg) Potency (min) Short-acting Cortisone 25 2 + 30 Hydrocortisone 20 2 + 9 0 (cortisol) Intermediate-acting Prednisone 5 1 + 60 Prednisolone 5 1 + 20 0 Methylprednisolone 4 0 180 Triamcinolone 4 0 300 Long-acting Dexamethasone 0.75 0 20 0 Betamethasone 0.6-0.75 0 300+ because cortisone must be activated to cortisol by the liver.8 Glucocorticoids can be administered through a va­ riety o f routes to elicit either a systemic or local response (Table 2). Intravenous administration rapidly delivers high concentrations o f the drug and is generally reserved Figure 1. The hypothalamic-pituitary-adrenocortical (HPA) for acute situations. Intramuscular administration is not axis. The normal diurnal cycle of cortisone secretion begins often recommended because these depot preparations with the release o f corticotropin releasing factor from the prolong HPA axis suppression.7 If tolerated by the pa­ hypothalamus which stimulates adrenocorticotropin (ACTH) tient, oral administration is the preferred route. Because secretion from the pituitary. ACTH stimulates the adrenals to of both rapid and complete absorption from the gastro­ release cortisol at a rate of about 20 mg per day with peak cortisol levels occurring in the morning. Through negative intestinal tract, dosing o f oral and parental glucocorti­ feedback, an increase in circulating cortisol (or its synthetic coids is equivalent.10 analogues) results in inhibition of this cycle. Numerous products are available for topical and local administration. Local administration of glucocorti­ commonly prescribed preparations are provided in Table coids permits the delivery o f high doses o f active drug to 1. Since glucocorticoids are pharmacologically active un­ the target tissue while minimizing the effects on other til metabolized, agents with a prolonged half-life are tissues and suppression o f the HPA axis.1’3’7 With all o f associated with both increased anti-inflammatory po­ these preparations, however, there is the potential for tency and a greater degree o f HP A axis suppression.1’4 systemic absorption of the glucocorticoid and subse­ Nevertheless, when these agents are administered in quent HPA axis suppression. equivalent anti-inflammatory doses, neither qualitative Numerous creams, ointments, and gels are available nor quantitative differences in the anti-inflammatory ef­ for direct application to inflamed or pruritic areas o f the fects are evident.6 Neither hepatic nor renal dysfunction skin. Ophthalmic drops and ointments are used in con­ appears to alter the pharmacokinetic disposition o f glu­ junctivitis and other inflammatory conditions o f the eyes. cocorticoids.7 Cortisone and hydrocortisone are rarely Inhaled preparations provide a direct, local action in the employed for long-term anti-inflammatory therapy be­ lungs and are used in patients with bronchial asthma who cause they have the highest sodium-retaining properties.1 require chronic treatment with corticosteroids in con­ Prednisone and cortisone lack glucocorticoid activ­ junction with other therapy. Intranasal preparations pro­ ity until they are converted to prednisolone and cortisol vide symptomatic relief o f seasonal or perennial rhinitis m the liver.1.8 Consequendy, in patients with acute hep­ and may prevent the recurrence o f nasal polyps. Intra- atitis or active chronic liver disease, availability o f the articular, intrasynovial, and intralesional administrations active compound is assured by administering pred­ of glucocorticoids provide local effects with minimal nisolone rather than prednisone.1’7’9 Similarly, an intra­ systemic toxicity. These local injections are usually re­ ocular injection of cortisone or its direct application to served for bursitis, tendinitis, and epicondylitis o f the the skin is ineffective in the treatment o f systemic disease knee, ankle, wrist, elbow, shoulder, hip, and phalangeal The Journal of Family Practice, Vol. 32, No. 5, 1991 513 Glucocorticoids Holland and Tayfa Table 2. Routes of Administration of Common Glucocorticoid Products Drug PO IV IM sc IA ID Top Inh Nasal Rect Ophth Otic Cortisone X — X ___ ___ ___ ____ ____ ___ ___ — ~ Hydrocortisone XXX XX — X —— X ___ x Prednisone X ————————— ___ Prednisolone X X X — X ————— X Methylprednisolone X X X — X — X — ——— Triamcinolone X — X — XXXX —— ___ Dexamethasone XXX — X — XXX — X Betamethasone XX X — XXX ——— ___ Flunisolide ——————— XX — ___ Beclomethasone ——————— XX — — __ PO— o ra l; IV — intravenous; IM — intramuscular; SC — subcutaneous; IA — intra-articular; ID — intradermal; Top— topical; Inh—respiratory inhaler; Nasal—intranasal solution R ea—rectal enema; Ophth— ophthalmic. joints. Glucocorticoid retention enemas are used as ad­ discontinuing the prolonged (more than 1 year) admin­ junctive therapy in the treatment o f ulcerative colitis, c4-7 istration o f supraphysiological doses of glucocorticoids, the functions of the hypothalamus and pituitary glands arc the first to recover, about 5 to 9 months following Mechanism of Action therapy.14 About 9 to 12 months are required for the adrenocortical response to return to normal. Following The precise mechanism by which glucocorticoids exert withdrawal o f prolonged doses o f glucocorticoids, at their anti-inflammatory