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TOPICAL GLUCOCORTICOIDS

Hydrocortisone, the first topically effective glucocorticoid, was introduced by Sulzberger and Witten in 1952.1 The success associated with hydrocortisone led to the design and development of an evergrowing list of more potent analogues. Currently, topical steroids are the most frequently prescribed of all dermatologic drug products. PHARMACOLOGY Modifications of cortisol, the basic molecule (Fig. 243-1) by addition or alteration of functional groups at certain positions, have led to compounds of varying potencies and side effects. Addition of a fluorine molecule at positions 6 and/or 9 enhances the potency of the steroid, but is accompanied by an increased mineralocorticoid activity.2 Substitution at the position 16 with an -hydroxyl (triamcinolone), -methyl (dexamethasone) or -methyl (betamethasone) increases efficacy without a concomitant increase in the sodium-retaining properties.3 The removal, replacement or masking of hydroxyl groups increases the molecule's lipophilicity, therefore rate of percutaneous absorption as well as the glucocorticoid receptor-binding activity. Masking of hydroxyl groups can be achieved by esterification at positions C16, C17, and C21 (i.e., butyric acid at position 17 in the hydrocortisone molecule yields hydrocortisone butyrate); or formation of acetonide groups by addition of a 16-hydroxy substituent, producing triamcinolone acetonide and fluocinolone acetonide. Replacement of the 21-hydroxyl group in the betamethasone molecule with a chlorine moiety, creates clobetasol 17propionate, the strongest molecule to date. The clinical potency of a topical corticosteroid depends not only on the inherent potency of the molecule but also on factors such as the vehicle and the nature of the skin onto which it is applied. The vehicle in which the steroid is incorporated may be as important as the steroid molecule itself because the vehicle affects the amount of steroid that is released in any given period of time (see Chap. 242). Very occlusive vehicles, such as ointments, potentiate glucocorticoid effects because they provide increased hydration of the stratum corneum and increase its permeability. By covering the skin with an occlusive dressing such as plastic wrap, this effect can be heightened as much as 100-fold. The solubility of the glucocorticoid in the vehicle also affects penetration into the epidermis. Propylene glycol is one agent commonly used to dissolve the glucocorticoid in the vehicle, and it is found in many topical glucocorticoid preparations.6 In general, compounds that contain higher amounts of propylene glycol tend to be more potent. Treatment of the skin prior to application of the topical steroid may also affect the absorption of the compounds into the skin. For example, use of keratolytics or fat solvents such as acetone enables increased penetration by disrupting the epidermal barrier. Tape stripping of the skin also increases the absorption of hydrocortisone by 78 to 90 percent. Topical glucocorticoid research has focused on strategies to optimize potency while minimizing side effects. One strategy is to develop compounds with enhanced anti-inflammatory effects and minimal unwanted atrophogenic and adrenal suppressive effects. In this sense, progress has been made with the development of glucocorticoid molecules that, while retaining high activity in the skin following topical application, are quickly broken down into inactive metabolites, thereby mitigating systemic and possibly some local toxic effects (soft glucocorticoids). Examples of these compounds

include fluticasone propionate, prednicarbate and methyl prednisolone aceponate.8 However, data on long-term safety following prolonged topical application of these agents is currently lacking. Research to develop a nonsteroidal compound with the same anti-inflammatory effects of glucocorticoids but without the side effects is currently ongoing.9 CLINICAL USES The clinical effectiveness of glucocorticoids is related to four basic properties: vasoconstriction, antiproliferative effects, immunosuppression, and anti-inflammatory effects. Topical steroids cause capillaries in the superficial dermis to constrict, thus reducing erythema. The ability of a given glucocorticoid agent to cause vasoconstriction usually correlates with its anti-inflammatory potency, and thus vasoconstriction assays are often used to predict the clinical activity of an agent. These assays in combination with double-blind clinical trials have been used to separate the topical glucocorticoids into seven classes based on potency. Class 1 includes the most potent, while class 7 contains the least potent. Table 243-1 lists many of the available topical glucocorticoids according to this classification.

The antiproliferative effect of topical glucocorticoids is mediated by inhibition of DNA synthesis and mitosis. Control of cellular proliferation is a complex process composed of cascades of stimulating influences that are counteracted by multiple inhibitory circuits. Many of these processes are probably influenced by glucocorticoids. The effectiveness of glucocorticoids, in part, may also be due to their immunosuppressive properties. The mechanisms responsible for immunosuppression are poorly understood. Several studies have

shown that glucocorticoids can cause mast cell depletion in the skin.11 This may explain the utility of topical glucocorticoids in patients with urticaria pigmentosa. Experiments also show that topical glucocorticoids cause a local inhibition of chemotaxis of neutrophils12 in vitro, and decrease the number of Ia+ Langerhans cells13 in vivo. In addition, several cytokines are directly affected by glucocorticoids, including interleukin (IL)-1, tumor necrosis factor-, granulocyte-macrophage colony-stimulating factor, and IL-8. These effects may also be a result of the steroid action on antigen presenting cells.14 It is believed that glucocorticoids exert their potent anti-inflammatory effects by inhibiting the formation of prostaglandins and other derivatives of the arachidonic acid pathway.15 It is known that glucocorticoids inhibit the release of phospholipase A2, the enzyme responsible for liberating arachidonic acid from cell membranes, thus inhibiting the arachidonic acid pathway. For many years it was believed that glucocorticoids caused macrophages and other cells to release a specific protein, lipocortin, that was thought to have a direct inhibitory action on phospholipase A2.16 Although lipocortins have since been purified and their genes cloned and sequenced, their role in the antiinflammatory action of glucocorticoids has been questioned.17 It is the current belief that glucocorticoids inhibit phospholipase A2 in cells by directly inducing phosphorylation of the enzyme.18 Other proposed mechanisms for the anti-inflammatory effects of glucocorticoids include inhibition of phagocytosis and stabilization of lysosomal membranes of phagocytizing cells. Certain variables must be considered when treating skin disorders with topical glucocorticoids. For example, the responsiveness of diseases to topical glucocorticoids varies. In this setting, diseases can be divided into the three categories shown in Table 243-2: highly responsive, moderately responsive, and least responsive. Highly responsive diseases will usually respond to weak steroid preparations; less-responsive diseases require medium potency steroids; and the least-responsive category requires high-potency topical steroids.

TABLE 243-2 Responsiveness of Dermatoses to Topical Application of Corticosteroids Before choosing a topical glucocorticoid preparation, one must consider the area of the body that is to be treated because regional differences greatly affect the activity of the topical agent. Penetration of the glucocorticoid varies according to the skin site, which, in turn, is related to the thickness of the stratum corneum and the vascular supply to the area. For example, penetration of topical steroids through the eyelids and scrotum is 4 times greater than for the forehead and 36 times greater than for

the palms and soles. Inflamed, moist, and denuded skin also shows increased penetration. Areas of the body where the skin is inherently thin not only allow for increased penetration of the drug but are more susceptible to develop side effects than other areas where the skin is thick (see Table 242-3). Potent topical steroids (classes 1 and 2) should rarely, if ever, be used in the areas with the highest level of penetration, such as the eyelids. Pediatric Uses Topical glucocorticoids are highly effective, and few side effects are observed when a low-potency preparation is used for brief periods of time without occlusion in children. Infants, however, are at an increased risk for side effects for several reasons. Because they have a higher ratio of skin surface area to body weight, application to a given area results in a greater potentially systemic dose of steroid. Infants may also be less able to metabolize potent glucocorticoids rapidly.20 Premature infants are especially at risk because their skin is thinner and the penetration rate of topically applied drugs is greatly increased.21 Application of topical steroids to the diaper area results in occlusion of the steroid by the diaper, and increased penetration occurs. Excess absorption of topical glucocorticoids can suppress endogenous cortisol production. Consequently, subsequent cessation of topical steroid therapy after an extended treatment period can result in an addisonian crisis characterized by nausea, anorexia, postural hypotension, and vascular collapse. Deaths from addisonian crisis have been reported with the use of topical steroids,22 and the risk of this occurring is greater in children. Chronic suppression of cortisol production can also lead to growth retardation. A morning plasma cortisol level can be performed to screen for adrenal suppression. If suppression is present, the child should be slowly weaned from the steroids to prevent these complications. Geriatric Uses Elderly patients similarly can have thin skin, which allows for increased penetration of topical glucocorticoids. They are also more likely to have preexisting skin atrophy secondary to aging and may be diaper-dependent, so the same precautions used in the treatment of infants should be used when treating elderly patients. Topical glucocorticoids should be used infrequently, for brief periods, or under close supervision in those patients with preexisting skin atrophy to avoid unwanted side effects. Uses in Pregnancy Appropriate human studies using topical glucocorticoids in pregnancy have never been undertaken. Studies in animals, however, show that topical steroids are systemically absorbed and may cause fetal abnormalities, especially when used in excessive amounts, under occlusive dressings, for prolonged periods of time, or when the more potent agents are used. However, numerous studies of pregnant patients taking systemic glucocorticoids throughout pregnancy show no increases in the incidence of fetal abnormalities. Most topical steroids are rated by the US Food and Drug Administration (FDA) as category C drugs, which implies that caution must be exercised when used in pregnancy. It is currently unknown whether topical glucocorticoids are excreted in breast milk; however, they should be used with caution in breast-feeding mothers and should never be used on the breasts prior to breast feeding.

DOSAGE SCHEDULES AND FORMULATIONS Twice-a-day topical application of glucocorticoids is recommended on the labels of most formulations, although no scientific evidence has ever established this as the optimal schedule. To decrease the risks of side effects, it is best to establish, with the aid of the patient, the longest elapsed time between successive applications that still controls the disease. This method may help to decrease the development of side effects and tachyphylaxis. Tachyphylaxis has been demonstrated in experimental conditions by diminished vasoconstriction, rebound of DNA synthesis, and recovery of histamine wheals after application of topical steroids in patients with a history of long-term topical steroid usage.23 Topical steroids come in many different vehicles and dosage forms. Ointments are water-insoluble mixtures of oil and petrolatum and are the best preparation when treating dry skin conditions because they provide the most moisture of the available preparations. They are also useful for treating conditions on areas of the body with thick skin, such as the palms and soles. The occlusive nature of the ointment and its ability to moisturize the stratum corneum allow for increased penetration and enhanced potency of the drug. Peanut oil has also been combined with steroids to form a preparation that is thinner and easier to apply while retaining the hydrating capability of ointments. However, patients may feel that ointments and oils are too greasy. New emollient creams have been devised that contain an increased amount of petrolatum but with less greasiness than ointments, and some patients find them more cosmetically appealing. Creams are suspensions of oil in water. They vary in their composition and generally are far less greasy than ointments, but they do not provide the same degree of hydration to the skin. Many patients find creams easier to spread on the skin and more cosmetically pleasing than ointments. However, creams may contain emulsifiers and preservatives that can lead to allergic reactions in some patients. Lotions are suspensions of oil in water and are similar to creams. They contain agents to help solubilize the glucocorticoids and to allow them to be spread more easily on the skin. Solutions contain no oil but are composed of water, alcohol, and propylene glycol. Gels are solid components at room temperature but melt on contact with the skin. Lotions, solutions, and gels have less penetration than ointments but are useful in treating hair-bearing areas such as the scalp where greasiness is cosmetically displeasing to the patient. Steroid-impregnated tapes are useful because they provide occlusion with increased penetration and provide protection of the skin lesion from manipulation, such as scratching, by the patient. Sprays containing steroids are available, and while they represent a convenient mode of applying these agents, the inefficiency of the delivery system is such that they are seldom recommended. More recently, foam products have been added to currently available topical formulations. They are highly efficacious, cosmetically superior, and well tolerated. When first dispensed, the foam is stable; but when applied to skin, body heat causes the foam structure to break down and the active ingredient is deposited on the skin with very little residue.24 (For a more complete discussion of vehicles for topical preparations, see Chap. 242.)

ADVERSE EFFECTS Side effects from the use of topical steroids have become more prevalent since the introduction of the higher potency topical steroids. Using these products on thin or denuded skin, on the elderly or pediatric population, or under occlusion increases the incidence of side effects. Striae and atrophy, the most commonly observed side effects, occur with prolonged use and are more likely to occur in areas of sweating, occlusion, or high penetration such as the axilla or groin. In general, atrophy does not occur until the agent has been used for 3 to 4 weeks and is usually reversible. Striae, which develop when the weakened skin is stretched, are not reversible. Prolonged treatment can also result in steroid acne, which is characterized by crops of dense, inflamed pustules in the same developmental stage. These lesions occur on the face, chest, and back. Perioral and periocular dermatitis have been associated with the use of topical steroids and usually improve with cessation of the steroid. Patients with rosacea who are given topical steroids may initially improve, but a severe rebound phenomenon consisting of edema and pustules may occur. For these reasons, in most situations steroid use should be discouraged in the treatment of rosacea and perioral and periocular dermatitis. Purpura, which represents easy bruising, may develop when steroids are used in areas of thin skin. Topical steroids can also cause suppression of the pituitaryadrenal axis. Growth retardation and iatrogenic Cushing's syndrome are known, but rare, complications of topical steroid therapy. Morning plasma cortisol serologic tests can be performed to screen for adrenal suppression. If these levels are abnormal, adrenal function can be assessed further by using the cosyntropin stimulation test. Most topical and systemic side effects are readily reversible if recognized early by the clinician. The incidence of side effects, however, can be significantly reduced if appropriate guidelines for topical steroid use are followed. Patients treated with topical glucocorticoids may develop a contact or irritant dermatitis to the steroid itself or, more commonly, to one of the ingredients used as a preservative. An increase in contact dermatitis caused by the steroid component has been reported.25 Most topical steroid ointments are free of preservatives and are less likely than other topical agents and steroid creams to cause an allergic or irritant contact dermatitis. The most common preservatives that cause allergic contact dermatitis include parabens, polyethylene glycol, and benzyl alcohol (Table 243-3). Fragrance and local anesthetics are also sensitizers that may be included in the topical preparations.

TABLE 243-3 Common Sensitizers in Topical Steroids

DRUG INTERACTIONS Topical glucocorticoids have few, if any, known drug interactions. For this reason they are often mixed with other topical medications, such as antifungals and antibiotics, to form combination products. Although a few combination products are available, development of new combination products has not been encouraged by the FDA. In fact, the FDA recently rejected new drug applications for combinations of topical antibacterials such as neomycin, bacitracin, and hydrocortisone, because the manufacturers were unable to provide proof of effectiveness of each component. However, many of these combination products are found in many countries outside the United States. Theoretically, there should be no need for a combination when each component can be obtained separately.

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