Section XIV - Dermatology

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The skin has many essential functions, including protection, thermoregulation, immune responsiveness, biochemical synthesis, sensory detection, and social and sexual communication. Therapy to correct dysfunction in any of these activities may be delivered topically, systemically, intralesionally, or through ultraviolet radiation.

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Section XIV. Dermatology Overview The skin has many essential functions, including protection, thermoregulation, immune responsiveness, biochemical synthesis, sensory detection, and social and sexual communication. Therapy to correct dysfunction in any of these activities may be delivered topically, systemically, intralesionally, or through ultraviolet radiation. Topical therapy is a convenient method of treatment, but its efficacy depends on understanding the barrier function of the skin, primarily within the stratum corneum. Corticosteroids and retinoids are important systemic and topical therapeutic agents for skin disease. Oral steroids are employed in high doses to treat very serious cutaneous eruptions, and, fortunately, structural modification of the hydrocortisone molecule has produced compounds of increased potency that now can be used topically to treat many dermatological diseases. Potent and efficacious retinoids for treatment of acne and psoriasis are administered orally, and modification of these molecules has resulted in topical agents that are being explored for their anticarcinogenic and antiaging effects. Oral antimalarials, chemotherapeutic agents, immunosuppressive agents, and antihistamines frequently are used for treatment of dermatological diseases. It is interesting that controlled ultraviolet (UV) radiation therapy is a frequent mode of treatment for psoriasis, pruritus, and atopic dermatitis, although UV radiation is itself responsible for the production of cutaneous cancers. However, the prophylactic use of sunscreens may reduce or prevent premalignant and malignant skin lesions induced by UV light, so their use is highly recommended. Major advances in the development and use of antifungal agents, antiviral agents, and antibacterial agents for skin diseases have clearly improved treatment options. Vitamin D analogs, retinoids, and anthralin are some of the topical agents used for psoriasis. Much of this chapter is organized according to specific dermatological disorders and drugs used in their treatment. Separate sections are devoted to glucocorticoids and retinoids because of their broad applications in dermatology. Agents with narrower spectra of uses are discussed under individual dermatological disorders. Dermatological Pharmacology: Introduction History of Dermatology The origins of dermatological pharmacology can be found in early Middle Eastern cultures. Early Egyptians recorded medical knowledge on special papyri, where mentions of alopecia and its treatment—consisting of equal parts of the fat of a lion, hippopotamus, crocodile, goose, snake, and ibex—are made. Indians used arsenic in the treatment of leprosy and a mixture of mercury and sulfur to treat pediculosis. A paste containing iron sulfate, bile, copper sulfate, sulfuret of arsenic, and antimony was used for pruritus of the scrotum. The Greeks under Hippocrates and the Romans under Celsus made many other contributions to the field of dermatology (King, 1927). As late as the end of the nineteenth century, dermatological therapy was still archaic by today's standards. At the first World Congress of Dermatology in Paris in 1889, one of the favorite treatments of tinea capitis was "dermabrasion with sandpaper followed by application of a solution of bichloride of mercury." Treatment of syphilis was thought to be best deferred until the secondary stage, at which time application of a 50% mercurous oleate
ointment was recommended (Shelley and Shelley, 1992). The dermatological pharmacopeia has grown rapidly in the past century, as our understanding of disease processes has improved. We have shifted our paradigm from the traditional axiom, which relied heavily on the physical characteristics of medications for their effect, to one in which chemical properties hold an equally important role. In the past, dermatological therapy consisted mainly of symptom relief. With advances in technology and knowledge, medications that target specific disease processes now are available. The Structure and Function of Skin The skin has many diverse functions, including protection, thermal regulation, sensory perception, and immune responses. The skin, in a strict sense, consists of the epidermis and its underlying dermis. However, one usually includes the soft tissue underlying the dermis in a discussion of the skin because of its close apposition to and tendency to react as a unit with the overlying skin. The top layer of the skin is the epidermis. It consists of keratinocytes, melanocytes (pigment), Langerhans' cells (antigen presentation), and Merkel cells (sensory). Keratinocytes, the proliferative portion of the epidermis, contain keratins, which provide internal structure. Each layer of the epidermis expresses different keratins, and keratins often are used as keratinocyte differentiation markers. Abnormal keratin expression is a feature of many skin diseases including psoriasis and some ichthyotic disorders. As keratinocytes mature and differentiate, they become larger and flatter and eventually lose their nuclei. The terminal point of keratinocyte differentiation is the formation of the stratum corneum. Formation of the stratum corneum is arguably the most important function of the epidermis. The stratum corneum, or horny layer, protects the skin against water loss, prevents the absorption of noxious agents, and can be thought of as consisting of bricks and mortar. Corneocytes form the "bricks," and barrier lipids form the "mortar." Corneocytes are formed by proteins found in keratinocytes and are located in the upper layers of the epidermis. Granular cells, which are immediately below the stratum corneum, contain basophilic structures called keratohyalin granules. These granules contain an inactive precursor protein called profilaggrin. Dephosphorylation and proteolysis of profilaggrin to filaggrin occurs as granular cells move into the horny layer. Filaggrin functions as a glue to bind the keratin filaments together to form macrofibrils and subsequently is broken down into free amino acids that form products that serve as UV filters and maintain skin hydration. Also, within granular cells, there are precursor proteins—such as involucrin, loricrin, keratolinin, and others—which are cross-linked by transglutaminases to form strong epsilon (gamma- glutamyl)–lysine isopeptide bonds forming the cornified cell envelope. Defects in filaggrin and transglutaminases are the basis of some ichthyotic disorders. Lamellar granules also are found within granular cells. These are membrane-bound organelles that contain probarrier lipids such as glycolipids, glycoproteins, and phospholipids. These lipids and proteins are secreted via exocytosis at the interface between the granular layer and the horny layer and are hydrolyzed to form ceramides and free fatty acids. Ceramides, fatty acids, and cholesterol, which are known as the barrier lipids, make up the intercellular mortar of the stratum corneum
Drug Delivery in Dermatological Diseases The skin is the largest organ of the body. It is unique in that it is easily accessible for the diagnosis and treatment of disease. For most dermatological conditions, the success or failure of treatment regimens is readily apparent to both the patient and physician. Medications can be delivered effectively to the skin by topical, systemic, and intralesional routes. Additionally, topical or systemic therapy can be combined with phototherapy to treat certain skin disorders such as psoriasis. Utilization of topical medications in skin disease provides many advantages. Most obvious, the skin is readily available for application of medications and the monitoring of therapy. Also, most topical medications have negligible systemic absorption and, therefore, few side effects. Drug/drug interactions are rare for this same reason. However, a good understanding of the pharmacokinetics of skin is necessary for successful use of topical medications. The primary barrier to absorption of exogenous substances through the skin is the stratum corneum. Passage through this outermost layer marks the rate-limiting step for percutaneous absorption. The major steps involved in percutaneous absorption include the establishment of a concentration gradient, which provides a driving force for drug movement across the skin; the release of drug from the vehicle into the skin—partition coefficient; and drug diffusion across the layers of the skin—diffusion coefficient. The relationship of these factors to one another is summarized in the following equation (Piacquadio and Kligman, 1998): J=Cveh·Km·D/x where J= rate of absorption; Cveh= concentration of drug in vehicle; Km= partition coefficient; D= diffusion coefficient; and x= thickness of stratum corneum. Physiological factors that affect percutaneous absorption include hydration, occlusion, age, intact versus disrupted skin, temperature, and anatomic site. For example, drug absorption is enhanced by improving hydration, the water content of the stratum corneum. This is achieved by decreasing transepidermal water loss through physical occlusion or by the application of an occlusive ointment. The permeability of skin is increased in preterm infants (Barker et al., 1987) and in elderly patients with thin skin as well as in anatomic areas of the body with thinner stratum corneum. Lastly, some substances are known to increase the penetration of drugs through the skin, including dimethyl sulfoxide (DMSO), propylene glycol, and urea. While intact skin provides a formidable barrier to percutaneous absorption, injured or diseased skin may significantly increase or decrease absorption. Tape stripping of the stratum corneum greatly increases percutaneous absorption. The thickened epidermal plaques of psoriasis may impede absorption of topical medications, whereas the broken surface of eczema may allow excessive absorption. In fact, topical absorption may be increased enough to cause systemic toxicity, such as hypothalamic-pituitary-adrenal axis suppression from systemic absorption of potent topical steroids. Vehicles Many factors influence the rate and extent to which topical medications are absorbed. Most topical medications are incorporated into bases or vehicles that bring drugs into contact with the skin. The vehicle chosen for a topical medication will greatly influence the drug's absorption, and vehicles themselves can have a beneficial effect on the skin if chosen
appropriately. Ideally, vehicles are easy to apply and remove, nonirritating, and cosmetically pleasing. In addition, the active drug must be stable in the chosen vehicle and must be released readily. Many early formulations of topical medications demonstrated less than optimal bioavailability due to insufficient knowledge of biophysical properties of drugs and vehicles, i.e., the partitioning of drugs from vehicles into skin. Hence, delivery of some older medications can be enhanced by dilution in an appropriate vehicle (Guin et al., 1993). The choice of an appropriate vehicle in topical preparations is of great importance. Since a vehicle makes up the greatest portion of a topical formulation, it has a significant impact on the absorption and hence therapeutic effect of the active drug. Factors that determine the choice of vehicle and the transfer rate of a drug across the skin are the drug's hydrophobic/hydrophilic partition coefficient, molecular weight, and water solubility. Except for very small particles, water-soluble ions and polar molecules do not penetrate intact stratum corneum. A vehicle can be classified as monophasic, biphasic, or triphasic, depending upon its components (Figure 65–1). Monophasic vehicles include powders, greases, and liquids. Powders, such as starch or talc, absorb moisture and reduce friction, and they have a soothing, cooling effect. However, powders adhere poorly to the skin and often clump, which limits their usefulness. Greases are protective. They are anhydrous preparations that are either water-insoluble or fatty, such as petrolatum (petroleum jelly), or water-soluble, such as polyethylene glycol. Fatty ointments are more occlusive than water-soluble ointments. An important point to note is that ointments are not by themselves hydrating; however, they restrict transepidermal water loss and hence preserve hydration of the stratum corneum. Figure 65–1. Topical Vehicle Formulations. (Modified from Polano, 1984, with permission.)
Liquids may be used as solvents for drugs, as they evaporate quickly and provide a cooling and drying effect. For example, lotions are liquid preparations in which medications are dissolved or suspended and are useful for hairy areas. Gels contain a liquid phase and have been converted into a semisolid by addition of a polymer. Gels can be thought of as microscopic pockets of liquids suspended in a mesh. Gels also are useful for hairy areas and tend to allow for greater penetration than do lotions. Powders, greases, and liquids can be combined to create biphasic and triphasic vehicles. Biphasic vehicles include "shake lotions" (lotion plus powder), pastes (powder plus grease), and creams (grease plus liquid). Shake lotions (e.g., calamine lotion) evaporate, leaving a residual powder, and are cooling and soothing. Pastes are ointments into which powder is incorporated. There are drying pastes, cream pastes, and protective pastes. Pastes are useful, for example, in the treatment of ulcers and chronic dermatoses. Creams can be emulsified oil- in-water preparations (e.g., vanishing creams) or water-in-oil emulsions (e.g., oily creams). With oil-in-water preparations, water evaporates, leaving a thin film of drug on the skin. Although the evaporation provides a cooling effect, it also makes oil-in-water preparations somewhat drying. Oil-in-water creams contain preservatives, which prevent microbial growth but can cause allergic contact dermatitis. Water-in-oil preparations contain less water and more oil than do vanishing creams. Hence, water-in-oil preparations are emollient and moisturizing. Triphasic vehicles consist of cream pastes or cooling pastes. Newer vehicles include liposomes and microparticles. Liposomes are concentric spherical shells of phospholipids in a water medium that may increase cutaneous bioavailability of the
medication and improve risk-benefit ratios. Liposomes most readily penetrate compromised epidermal barriers (Korting et al., 1991). There are two stages of liposomal drug release. In the first stage, liposomes remain in a liquid state and absorption is slow. In the second stage, the preparation dries and intercalates in the lipids of the skin's surface and diffuses into the stratum corneum. Microparticles are polymer-based microstructures in which drugs can be trapped. Microparticles allow for metered drug release and can have the advantage of causing less irritation. Variability in Topical Preparations Substitution of generic for trade-name topical medications is commonplace. However, generic topical preparations and name-brand products may not be equivalent. Criteria used to evaluate the equivalence of two topical preparations include pharmaceutical or chemical equivalence, i.e., the same active ingredient is contained in both preparations; the bioequivalence of two preparations, which compares the bioavailability of the active ingredient in two different preparations; and the therapeutic efficacy and toxicity of two different preparations of the same active ingredient. There are many difficulties in assessing the bioavailability of topical agents. Blood levels typically are very low and are not reliable indicators of drug availability in the skin. Indeed, topical medications are intended to deliver optimal dosages of medication to the skin with minimization of systemic absorption (Piacquadio and Kligman, 1998). Differences in bioequivalence among generic and brand-name products have occurred with topical steroids as measured by vasoconstrictor assays (see below). Although bioequivalence may be established by vasoconstrictor assays, this may not equate with therapeutic equivalence (Olsen, 1991). One problem that arises in the use of either generic or brand-name topical steroids is the variability of vehicles used. Although active ingredients may be the same, the vehicles may differ significantly. Different inert ingredients in either generic or brand-name products may have an adverse impact on patients, causing allergic reactions or skin irritation (Jackson et al., 1989). There also may be variations in therapeutic effect due to variations in rate or extent of absorption among products or to variable shelf lives. Systemic and Intralesional Administration Systemic administration of medication in dermatology usually involves oral ingestion but also can involve the intramuscular route (e.g., methotrexate, glucocorticoids). Systemic medications are used when therapeutic effects cannot be obtained with topical medication. A good example is the treatment of onychomycosis (fungal infection of the nail). Topical medications do not adequately penetrate the hard keratin of the nail; hence, systemic therapy is necessary for successful treatment. Systemic absorption of oral and parenteral medications is discussed in Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination. Intralesional medications are used mainly for inflammatory lesions but can be used for treatment of warts and neoplasms. Medications injected intralesionally have the advantage of direct contact with the underlying pathology, no first-pass metabolism, and the formation of a depot of drug. Systemic absorption of medication varies with the drug being used. For instance, when 20 mg of intralesional triamcinolone acetonide is injected, plasma cortisol levels can be suppressed for a few days. In considering the use of intralesional medications, it
is important to be cognizant of the systemic absorption of the medication being used. In summary, when treating cutaneous diseases, it is not only the drug selected but also factors such as route of administration, integrity of normal versus abnormal barrier functions of the skin, and the vehicle that are important in determining ultimate clinical efficacy. Glucocorticoids Topical Agents Shortly after the synthesis of hydrocortisone in 1951, topical steroids were recognized as effective agents for the treatment of skin disease (Sulzberger and Witten, 1952). New halogenated glucocorticoids with greatly enhanced potency were synthesized in the mid-1950s. With the development of appropriate vehicles, these agents rapidly became the mainstay of therapy for many inflammatory skin diseases. Topical glucocorticoids have been grouped into seven classes in order of decreasing potency (Table 65–1). Potency is measured using a vasoconstrictor assay, in which an agent is applied to skin under occlusion and the area of skin blanching assessed, and the psoriasis bioassay, in which the effect of steroid on psoriatic lesions is quantified (McKenzie and Stoughton, 1962; Dumas and Scholtz, 1972). Other assays of steroid potency involve suppression of erythema and edema following experimentally induced inflammation. Therapeutic Uses Many inflammatory skin diseases respond to topical or intralesional administration of glucocorticoids. Absorption varies among different body areas; the steroid to be used is chosen on the basis of its potency, the site of involvement, and the severity of the skin disease. Often, a more potent steroid is used initially, followed by a less potent agent. Most practitioners become familiar with one or two drugs in each class so as to deliver the appropriate strength of drug. Twice-a-day application is sufficient; more frequent application does not improve response (Yohn and Weston, 1990). In general, hydrocortisone or an equivalent is the most potent steroid used on the face or in occluded areas such as the axilla or groin. Tachyphylaxis can occur, and switching to a different glucocorticoid or using the drug less frequently often can restore sensitivity to the drug (Singh and Singh, 1986). Intralesional injection of glucocorticoids usually is done with insoluble preparations of triamcinolone [triamcinolone acetonide (KENALOG-40, others) and triamcinolone hexacetonide (ARISTOSPAN)], which solubilize gradually and therefore have a prolonged duration of action. The hexacetonide can further prolong the therapeutic effect. Intralesional steroids are particularly valuable if the inflammatory area is in fat, as in an inflammatory scalp alopecia or panniculitis. Intralesional injections also may be used to deliver high doses of medication to more superficial inflammatory dermatoses, including psoriasis, discoid lupus, and inflamed cysts. Toxicity and Monitoring Use of higher-potency topical glucocorticoids is associated with increased local and systemic toxicity. Locally there is skin atrophy, striae, telangiectasias, purpura, acneiform eruptions, perioral dermatitis, overgrowth of skin fungus and bacteria, hypopigmentation in pigmented
skin, and rosacea. The striae are most common in intertriginous areas but can occur diffusely. The perioral dermatitis and rosacea occur on the face when withdrawal of the steroid is attempted; for this reason, use of halogenated glucocorticoids on the face should be avoided. Long-term application near the eye can cause cataracts or glaucoma. There is sufficient absorption of the most highly potent topical glucocorticoids through inflamed skin to cause systemic toxicity, including suppression of the hypothalamic-pituitary-adrenal axis and growth retardation, particularly in young children (Bondi and Kligman, 1980; Wester and Maibach, 1993). Factors that increase systemic absorption include the amount of steroid applied, the extent of the area treated, the frequency of application, the length of treatment, the potency of the drug, and the use of occlusion. Intralesional glucocorticoids can cause cutaneous atrophy and hypopigmentation. To minimize this atrophy, doses on the face usually are limited to 1 to 3 mg/ml of triamcinolone acetonide. Systemic side effects, including suppression of the hypothalamic-pituitary-adrenal axis, usually are minimal if total doses are kept below 20 mg of triamcinolone acetonide per month. Systemic Agents Therapeutic Uses Systemic glucocorticoid therapy is used for a number of severe dermatological illnesses (Table 65–2). In general, it is best to reserve glucocorticoids for acute treatment of transient illnesses or for management of life-threatening dermatoses. Chronic therapy of atopic dermatitis with oral glucocorticoids is problematic, given the side effects associated with their long-term use (see Chapter 60: Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones ). Recent studies suggest that glucocorticoids do not prevent development of postherpetic neuralgia (Wood et al., 1994). Daily morning dosing with prednisone usually is necessary initially, although occasionally split daily doses are used to enhance efficacy. Fewer side effects are seen with every-other-day dosing, and prednisone is tapered to every other day as soon as possible. The intramuscular route is occasionally used to assure compliance, although this route is not recommended because of erratic absorption and prolonged hypothalamic-pituitary-adrenal axis suppression associated with the longer-acting preparations typically injected. Pulse therapy with large daily doses of methylprednisolone sodium succinate (SOLU-MEDROL) is given intravenously for resistant pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, organthreatening systemic lupus erythematosus, and dermatomyositis (Werth, 1993). The dose usually is 0.5 to 1.0 g given over 2 to 3 hours. More rapid infusion has been associated with increased rates of hypotension, electrolyte shifts, and arrhythmias. Toxicity and Monitoring Oral glucocorticoids have numerous systemic effects, as discussed in Chapter 60: Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones. Most side effects are dose-dependent. Long-term use is associated with a number of complications, including psychiatric problems, cataracts, myopathy, avascular necrosis, and hypertension. In addition, patients with psoriasis who are taking glucocorticoids may have a pustular flare as the
medication is tapered. Patients treated with multiple intramuscular glucocorticoid injections have the same side effects as those treated orally. Pulsed intravenous glucocorticoids can cause hypo tension or hypertension, hyperglycemia, hypokalemia or hyperkalemia, anaphylactic reactions, acute psychosis, seizures, and sudden death. Congestive heart failure and pulmonary edema can develop. After brief high-dose treatment is stopped, a steroid withdrawal syndrome with transient arthralgias, myalgias, and joint effusions can develop, but without overt addisonian crisis (Kimberly, 1988). Retinoids Retinoids include natural compounds and synthetic derivatives of retinol that exhibit vitamin A activity (see Chapter 64: Fat-Soluble Vitamins: Vitamins A, K, and E). Retinoids have many important and diverse functions throughout the body, including roles in vision, regulation of cell proliferation and differentiation, bone growth, immune defense, and tumor suppression (Chandraratna, 1998). Because vitamin A affects normal epithelial differentiation, it was investigated as a treatment for cutaneous disorders but was abandoned initially because of unfavorable side effects. With the synthesis of multiple retinoids, agents with specific effectiveness and decreased toxicity were developed. Small changes in structure resulted in major changes in function (Figure 65–2). First-generation retinoids include retinol, tretinoin (all trans-retinoic acid), isotretinoin (13-cis-retinoic acid), and alitretinoin (9-cis- retinoic acid). Second-generation retinoids, which include etretinate and its metabolite acitretin, were created by alteration of the cyclic end group. Third-generation retinoids contain further modification and are called arotinoids. Members of this generation include tazarotene and bexarotene. Adapalene is a derivative of naphthoic acid with retinoid-like properties; chemically it does not fit precisely into any of the three generations of retinoids. Figure 65–2. Three Generations of Retinoids. Major structural changes of each generation are indicated in blue.
An understanding of retinoid receptors is necessary before the actions of retinoids in the regulation of cell proliferation and differentiation can be discussed. Two families of retinoid receptors exist. Retinoic acid receptors (RARs) are members of the thyroid/steroid superfamily of receptors. RARs are further divided into alpha, beta, and gamma subtypes. The second family of retinoid receptors is the retinoid X receptor family (RXRs). Retinoid X receptors also are subdivided into alpha, beta, and gamma subtypes. Human skin contains mainly RAR beta and gamma receptors. Retinoids regulate gene transcription through activation of nuclear receptors. Retinoids (ligands) bind transcription factors (nuclear receptors), and the ligand-receptor complex formed then binds to the promoter region of a target gene (Saurat, 1999). The gene products formed contribute to both desirable pharmacological effects and unwanted side effects (Shroot, 1998). The structure of a particular retinoid determines which type of retinoid receptor will be bound and hence what pharmacological effects will be produced. The basic structure of the retinoid molecule consists of a cyclic end group, a polyene side chain, and a polar end group. Alteration of side chains and end groups creates the various classes of retinoids. First- and second-generation retinoids are able to bind several retinoid receptors due to the flexibility imparted by their alternating single and double bonds. This relative lack of receptor specificity may lead to greater side effects. Third-generation retinoids are much less flexible
than first- and second-generation retinoids and, therefore, interact with fewer retinoid receptors (Chandraratna, 1998). Acute retinoid toxicity is similar to vitamin A intoxication. General side effects of retinoids include dry skin, nose bleeds from dry mucous membranes, conjunctivitis, and hair loss. Less frequently, musculoskeletal pain, pseudotumor cerebri, or mood alterations have been observed. Oral retinoids are potent teratogens and cause severe fetal malformations. Systemic retinoids should be used with great caution in females of childbearing potential. Retinoids are used in the treatment of many diverse diseases and are effective in the treatment of inflammatory skin disorders, skin malignancies, hyperproliferative disorders, photoaging, and many other disorders (Table 65–3). Their uses in some of these disorders, such as psoriasis and acne, are discussed below. Pruritus The term pruritus is derived from the Latin prurire, which means "to itch" (Kantor, 1996). Pruritus occurs in a multitude of diverse disorders ranging from the itch of dry skin (xerosis) to the itch of internal malignancy (Table 65–4). The treatment of pruritus varies greatly with the disorder in which it is seen. Many treatment modalities are available for pruritus (Table 65–5). General, non-disease-specific measures can be helpful in treating most cases of pruritus (Table 65–6). General measures usually are sufficient for xerosis. Inflammatory disorders such as atopic dermatitis, contact dermatitis, and lichen simplex chronicus respond better to treatment with potent topical steroids and antihistamines. Atopic dermatitis is discussed below. Cholestasis-associated pruritus may respond to cholestyramine (QUESTRAN; see Chapter 36: Drug Therapy for Hypercholesterolemia and Dyslipidemia), ursodeoxycholic acid (ACTIGALL), ondansetron (ZOFRAN; see Chapter 38: Prokinetic Agents, Antiemetics, and Agents Used in Irritable Bowel Syndrome), or rifampin (see Chapter 48: Antimicrobial Agents: Drugs Used in the Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy; Connolly et al., 1995). Recently, nalmefene (REVEX) (20 mg twice per day; see Chapter 23: Opioid Analgesics) has been shown to be effective in cholestatic pruritus (Bergasa et al., 1999). The pruritus of uremia is treated most effectively with ultraviolet B radiation (UVB). Prurigo, a ubiquitous disorder associated with itchy nodules of the skin, is notoriously difficult to treat. In addition to topical and intralesional steroids, prurigo may respond to the opioid antagonist naltrexone (see Chapter 23: Opioid Analgesics) at a dose of 50 mg per day (Metze et al., 1999) or to the proton pump inhibitor omeprazole (see Chapter 37: Agents Used for Control of Gastric Acidity and Treatment of Peptic Ulcers and Gastroesophageal Reflux Disease; Ohtsuka et al., 1999). Atopic Dermatitis Atopic dermatitis is an inflammatory condition of the skin that commonly begins in infancy and childhood and can extend into the adult years. In some geographic regions, up to 10% of children have atopic dermatitis, and the incidence is increasing (Zaki et al., 1996). Environmental pollutants and indoor allergens, such as dust mites, may be responsible for
this increase. Hallmarks of atopic dermatitis are itchy papules and plaques. In infants, lesions occur on the face and extensor surfaces, which are common sites of trauma. In later childhood and adulthood, flexural involvement is more common. Acute, subacute, and chronic lesions occur. Acute lesions consist of itchy papulovesicles or wheals. Subacute papules and plaques show excoriation and chronic plaques are thickened and dry. Physical traits of atopic children include redundant folds of the lower eyelid, fissured lips, and increased palmar skin markings. Infections are common in atopic children, particularly herpes simplex, molluscum contagiosum, fungus, and Staphylococcus aureus. Up to 90% of lesions of atopic dermatitis are colonized by S. aureus. The goals of treatment in atopic dermatitis are skin hydration, decreased bacterial colonization, control of itching, decreased inflammation, and elimination of exacerbating factors. Cutaneous hydration helps to eliminate fissures and cracks in the skin from which pathogens may enter. Hydration consists of soaking in a lukewarm bath, followed immediately by the application of thick emollient creams. Glucocorticoids Topical glucocorticoids are useful for decreasing inflammation. Higher-potency topical steroids are indicated for thick, chronically rubbed plaques on the extremities. Lower potency, nonfluorinated topical steroids should be used for facial lesions for short (less than 2 weeks) periods of time. Potential side effects of topical steroids include striae and atrophy of the skin. Topical steroids should be used no more than 2 or 3 times per day and should be discontinued as quickly as possible to avoid potential side effects. Antihistamines Oral antihistamines, particularly H1-receptor antagonists (see Chapter 25: Histamine, Bradykinin, and Their Antagonists) with sedative properties, are useful for the control of pruritus. Hydroxyzine hydrochloride (ATARAX) is given in a dose of 0.5 mg/kg every 6 hours and provides sedation. Other sedative H1 blockers include diphenhydramine (BENADRYL; others), promethazine (PHENERGAN), and cyproheptadine (PERIACTIN). Nonsedative antihistamines include cetirizine (ZYRTEC), loratadine (CLARITIN), and fexofenadine hydrochloride (ALLEGRA). Doxepin, which has both tricyclic antidepressant and sedative antihistamine effects (see Chapter 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders), is a good alternative for severe pruritus. Doxepin also is available as a 5% cream (ZONALON), and it can be used effectively in conjunction with low- to moderate-potency topical steroids. Leukotriene Receptor Antagonist The leukotriene antagonist zafirlukast (see Chapter 28: Drugs Used in the Treatment of Asthma), in a dosage of 20 mg twice daily, has improved atopic dermatitis in some patients. Side effects include pharyngitis, headache, and infrequent elevation of alanine aminotransferase values (Carucci et al., 1998). Immunosuppressive Agents Immunosuppressive agents (see Chapter 53: Immunomodulators: Immunosuppressive
Agents, Tolerogens, and Immunostimulants) should be considered when hydration, topical steroids, and antihistamines have not provided adequate clearing of atopic dermatitis. Cyclosporine (NEORAL; others) is used in many dermatological and autoimmune diseases. Although used in the treatment of atopic dermatitis, cyclosporine is not approved by the United States Food and Drug Administration (FDA) for the purpose. T-cell activation and proliferation are inhibited by cyclosporine (Faulds et al., 1993). The initial dose of cyclosporine usually is 5 mg/kg per day, which allows for rapid improvement, with maintenance dosage of 3 mg/kg per day (Zonneveld et al., 1996). Alternatively, it has been suggested that a body weight–independent dose of 150 mg per day is both efficacious and well tolerated (Czech et al., 2000). Cyclosporine appears to be safe and effective for children when given in short courses (Zaki et al., 1996). Potential side effects of cyclosporine therapy include nephrotoxicity, hypertension, gingival hyperplasia, and hypertrichosis. Complete blood counts, blood pressure measurements, and serum creatinine levels should be monitored regularly. A promising new topical immunosuppressive agent is tacrolimus (PROTOPIC), which was isolated from Streptomyces tsukubaenis in Tsukuba, Japan, in 1984. Tacrolimus is a neologism composed of the words Tsukaba Macrolide immunosuppressive, and the oral form currently is used in kidney, liver, and heart transplants (see Chapter 53: Immunomodulators: Immunosuppressive Agents, Tolerogens, and Immunostimulants). Tacrolimus binds to an intracellular receptor in T cells that interferes with cytokine-mediated processes active in atopic dermatitis. Topical tacrolimus currently is being evaluated in clinical trials and shows great promise in the treatment of refractory atopic dermatitis (Ruzicka et al., 1999). Psoriasis Psoriasis is characterized by epidermal hyperproliferation overlying immune-mediated dermal inflammation. Clinically, this results in erythematous scaling plaques most commonly present on the elbows, knees, and scalp. The cracking, scaling plaques of psoriasis may be widespread and even painful, with the potential for significant disability. Flare-ups of psoriasis can occur randomly but have been known to follow periods of physical and emotional stress, cutaneous trauma, infection, and as a reaction to certain medications, including -adrenergic receptor antagonists, lithium, antimalarials, and systemic steroids (Christophers and Mrowietz, 1999). The selection of therapy for psoriasis is multifactorial. The overall health status of the patient must be taken into account, particularly hepatic and renal function, childbearing potential, and the presence or absence of psoriatic arthritis. Another major consideration is the percent of body surface area involved. For practical purposes, patients with less than 15% body surface involvement can be treated effectively with topical agents. A notable exception to this is significant involvement of the hands or feet, which may be recalcitrant to topical treatment. Topical Agents Used in Treatment of Psoriasis Topical therapy for psoriasis includes multiple options (Figure 65–3), the first of which are emollients to soften and moisturize psoriatic plaques. Topical keratolytic agents, formulated with urea or salicylic acid, also are useful in the treatment of localized or limited psoriasis; and topical coal tar preparations in the form of ointments, emollient-base creams, lotions, and shampoos have been used over the past century. Topical steroids are the mainstay of treatment for localized psoriasis. A vitamin D analog, calcipotriene, is useful for the topical
treatment of psoriasis, as a solution, an ointment, or a cream. Anthralin and the topical retinoid tazarotene also are beneficial. These topical agents will be discussed below in more detail. Figure 65–3. Treatment of Psoriasis. In psoriasis, a hyperproliferative disease, all four modes of therapeutic delivery are used: topical therapy, phototherapy, intralesional therapy, and systemic therapy. Major normal cutaneous structures are shown. PUVA, psoralens and ultraviolet A; UVB, ultraviolet B. Coal Tar Coal tar has a limited effect when employed as the sole treatment for psoriasis, and it is now mainly combined with ultraviolet light in the 290 to 320 nm range (UVB) for this indication. It is manufactured as a byproduct of the processing of coke and gas from bituminous coal and is extremely complex, rich in polycyclic hydrocarbons, and variable in composition. Little is known about its mode of action, which may be related to antimitotic effects (Lowe et al., 1983). Coal tar is phototoxic in the ultraviolet light range of 320 to 400 nm (UVA) and visible ranges, with the action spectrum lying between 340 and 430 nm. Exposure of the skin in this range produces erythema and smarting, "tar smarts," which prevent exploitation of coal tar's photodynamic potential for the treatment of psoriasis. Coal tar ointment contains crude coal tar, usually 2% to 5%, dispersed in petroleum jelly. The use of coal tar with daily UVB irradiation—known as the Goeckerman regimen—is a highly effective therapy for psoriasis. It improves the efficacy of suberythemogenic UVB, probably by additive effects rather than by photoactivation of the tar. More refined extracts
of tars are formulated as solutions, gels, shampoos, and baths, usually with limited efficacy as primary agents. Folliculitis is the primary side effect of coal tar. Irritation and allergic reactions are rare; and, although coal tar has been shown to be a carcinogen in animal experiments, carcinomas provoked by clinical application are rare (Dodd, 1993). Calcipotriene Calcipotriene (DOVONEX), a vitamin D analog, was approved for the topical treatment of psoriasis in 1993. Chance observation of improvement of psoriasis in an osteoporotic patient receiving an oral derivative of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], the active form of vitamin D (see Chapter 62: Agents Affecting Calcification and Bone Turnover: Calcium, Phosphate, Parathyroid Hormone, Vitamin D, Calcitonin, and Other Compounds ), stimulated interest in the development of the drug as an antipsoriatic agent (Morimoto and Kumahara, 1985). 1,25-(OH)2D3 has a major role in the maintenance of calcium homeostasis but is now known to be involved in many other physiological functions. The vitamin binds to an intracellular receptor, a member of the gene superfamily including steroid, thyroid hormone, and retinoid receptor genes. The receptor–vitamin D complex binds to specific genes and modulates and controls transcription. The receptor is present in human epidermal keratinocytes, dermal fibroblasts, islets of Langerhans' cells, macrophages, and T lymphocytes. At physiological concentrations, 1,25-(OH)2D3 causes a decrease in the proliferation and an increase in the morphologic and biochemical differentiation of cultured keratinocytes (Smith et al., 1986). In clinical studies, both oral and topical 1,25-(OH)2D3 are effective antipsoriatic agents, but their use is limited by induction of hypercalciuria (Smith et al., 1988; Langner et al., 1992). Calcipotriene is a synthetic 1,25-dihydroxyvitamin D3 analog with a double bond and ring structure on the side chain as follows: These modifications result in rapid transformation into inactive metabolites. This drug is 200- times less potent than 1,25-(OH)2D3 in causing hypercalciuria and hypercalcemia, and its affinity for the vitamin D receptor is equal to that of 1,25-(OH)2D3. Efficacy in psoriasis has been demonstrated in double-blind, placebo-controlled studies (Kragballe, 1989).
Calcipotriene is applied twice daily to plaque psoriasis on the body. Improvement is detectable within 1 to 2 weeks, and maximum clinical response occurs within 6 to 8 weeks. Some improvement takes place in most patients, with complete resolution occurring in up to 15%. The drug is slightly more effective than either the corticosteroid betamethasone 17- valerate or short-contact anthralin treatment. Maintenance therapy usually is necessary, and tachyphylaxis does not occur (Kragballe, 1992). Reports of hypercalcemia with calcipotriene are rare and usually have been associated with excessive use of the drug (Hardman et al., 1993). Calcipotriene should be used with caution in intertriginous areas because of facilitated absorption, which results in irritation. Routine laboratory monitoring is not necessary if usage guidelines are followed. It is available in an ointment, cream, or solution. Anthralin Chrysarobin, the active ingredient of Goa powder, was first used in 1877 for the treatment of psoriasis. It was replaced in 1916 by the synthetic compound anthralin (1,8-dihydroxy-9- anthrone; dithranol; DRITHOCREME), which has the following structure: The anthralin molecule is unstable, having an oxidizable center at C10 that leads to the formation of degradation products that produce the characteristic violet-brown staining of skin and clothes. The mechanism of the antipsoriasis effect of anthralin is unknown, but it inhibits cellular respiration by inactivation of mitochondria (Reichert et al., 1985). Anthralin is applied topically in concentrations of 0.1% to 1.0%. The drug also can be prepared in higher strengths in petroleum jelly or zinc paste with the addition of salicylic acid as an antioxidant. Standard therapy is to apply a lower concentration (0.1%) for several hours for at least a week and then gradually increase the concentration. A modification of this treatment, called short-contact therapy, is possible because anthralin penetrates damaged skin faster and to a greater extent than normal skin (Schaefer et al., 1980). Therefore, application for 1 hour or less optimizes the therapeutic effect while minimizing the irritation. Short-contact therapy is initiated with higher concentrations (0.25% or 0.5%) applied for 20 to 30 minutes, and the concentration is increased more rapidly. With either the standard or short-contact regimens, the medication must be completely removed by bathing or shampooing at the end of the contact time. The primary side effects of anthralin are staining and irritation of the uninvolved skin. Because of individual variation in skin sensitivity, close monitoring of irritation and careful progression of treatment are necessary. Treatment of intertriginous and facial lesions is not advisable, and permanent staining of clothes and bathroom fixtures is annoying. In an effort to decrease irritation and staining, anthralin also has been microencapsulated in crystalline monoglycerides.
Tazarotene The topical retinoid tazarotene (TAZORAC), an acetylenic class of retinoid, has been developed in the form of a gel to be used for the treatment of psoriasis and acne vulgaris (Duvic and Marks, 1998). This retinoid binds to all three members of the retinoic acid receptor family. In mice, tazarotene has been shown to block ornithine decarboxylase activity, which is associated with cell proliferation and hyperplasia. In cell culture, it has been shown to suppress a marker of epidermal inflammation and to inhibit cornification of the keratinocyte. Tazarotene gel, applied once a day to dry skin, may be used as monotherapy or in combination with other medications, such as topical steroids, for the treatment of localized plaque psoriasis. This is the first topical retinoid to be indicated for the treatment of psoriasis. Side effects of burning, itching, and skin irritation may be noted by some patients. Patients should avoid exposing treated areas to sun or sun lamps unless medically necessary. In as much as this topical drug is a member of the retinoid family, women of childbearing age should avoid pregnancy while using this medication. Systemic Agents Used in Treatment of Psoriasis The use of systemic medications for the treatment of psoriasis may be indicated by the extent or severity of the disease. Involvement of body surface area greater than 15%, inflammation of hands or feet, pustular outbreaks, or arthritis all can be indications for systemic treatment. Some cancer chemotherapeutic agents have been used with good results in psoriasis, especially methotrexate, but also 6-thioguanine and hydroxyurea. The systemic retinoid acitretin can be used either as monotherapy or in conjunction with PUVA. Immune modulators have become important in the treatment of psoriasis, especially as the driving force in the pathophysiology of psoriasis appears to center on the T cell (Gottlieb et al., 1995). Notably absent from the list of recommended systemic agents for the treatment of psoriasis are glucocorticoids. While short-lived reductions in inflammation may be seen with use of systemic steroids, unpredictable and severe exacerbations of plaque-type and pustular psoriasis have occurred following the use of these drugs. Cytotoxic Agents The antimetabolite methotrexate (RHEUMATREX) is an analog of folic acid that competitively inhibits dihydrofolate reductase (see Chapter 52: Antineoplastic Agents). Methotrexate has made a significant impact on the treatment of widespread and severe psoriasis. Its primary therapeutic mechanism centers on suppression of immune-competent cells in the skin, principally T cells (Jeffes et al., 1995). By virtue of immune suppression, methotrexate dampens signals for epidermal inflammation and hyperproliferation. It is useful in treating a number of cutaneous conditions including psoriasis, pityriasis lichenoides, lymphomatoid papulosis, pemphigus vulgaris, pityriasis rubra pilaris, lupus erythematosus, and dermatomyositis. A usual starting dose for methotrexate therapy is 5 to 7.5 mg per week. This dose may be gradually increased up to 20 to 30 mg per week if needed. When the drug is taken orally, the weekly dose is divided into three doses given at 12-hour intervals to optimize absorption. Doses must be decreased for patients with impaired renal clearance. Methotrexate should
never be coadministered with trimethoprim–sulfamethoxazole or other drugs that can cause bone marrow suppression, as severe or possibly fatal bone marrow suppression can occur with such combinations. Fatalities have occurred during concurrent treatment with methotrexate and nonsteroidal antiinflammatory agents. Methotrexate exerts significant antiproliferative effects on the bone marrow; therefore, complete blood counts should be monitored serially. Physicians administering methotrexate should be familiar with the use of folinic acid (leucovorin) to "rescue" patients with hematologic crises caused by methotrexate-induced bone marrow suppression. Careful monitoring of liver function tests is necessary but may not be adequate to identify early hepatic fibrosis in patients taking methotrexate. Hepatic fibrosis from methotrexate appears to be more common in psoriasis than in rheumatoid arthritis. Consequently, liver biopsy is recommended when the cumulative dose reaches 1.5 g. A baseline liver biopsy also is recommended for those patients with increased risk for hepatic fibrosis, such as history of alcohol abuse or hepatitis B or C. Patients with significantly abnormal liver function tests, symptomatic liver disease, or evidence of hepatic fibrosis should not use this drug (Roenigk et al., 1998). Hydroxyurea and 6-thioguanine also are used occasionally in the treatment of psoriasis. Neither of these treatments is as effective as methotrexate, but either one can be useful in situations where methotrexate is contraindicated due to liver disease. Both drugs may cause significant bone marrow suppression; therefore, careful monitoring is required (Leavell et al., 1973; Zackheim et al., 1994). Acitretin Acitretin (SORIATANE) is the major metabolite of etretinate, an aromatic retinoid. Both drugs have been shown to be useful in the treatment of psoriasis, including pustular and erythrodermic psoriasis. Etretinate, an early retinoid which is no longer commercially available, has an elimination half-life of 100 days due to its high lipophilicity. Acitretin, however, has an elimination half-life of two to three days. Unfortunately, acitretin is readily esterified to produce etretinate in vivo, and this reaction is further enhanced by alcohol (Katz et al., 1999). The optimal dosing range for acitretin in adults is 25 to 50 mg per day. This gives an appropriate balance of efficacy with an acceptable level of side effects. Improvement of plaque psoriasis occurs gradually, requiring up to three to six months for optimal results. As a monotherapy, acitretin has an overall rate of complete remission of less than 50% (Ling, 1999); response rates are higher when the drug is used in combination with ultraviolet light (Lebwohl, 1999). Pustular and erythrodermic psoriasis usually respond more rapidly than common plaque psoriasis at doses of 10 to 25 mg per day. Excellent control of these conditions usually can be achieved with acitretin (Goldfork and Ellis, 1998). Toxicity related to acitretin can resemble hypervitaminosis A. Common side effects include dry skin and mucous membranes, xerophthalmia, and hair thinning. Less frequently, arthralgias and decreased night vision have been noted. While other side effects are occasionally reported, serious side effects, such as hepatotoxicity or pseudotumor cerebri, are rare (Katz et al., 1999). Acitretin is a potent teratogen and may cause major human fetal abnormalities. This drug
should not be used by females who are pregnant or who intend to become pregnant during therapy or at any time for at least three years following discontinuation of therapy. Patients should not donate blood for transfusion during acitretin therapy and for three years following therapy to avoid exposing a pregnant recipient's fetus to the drug. Laboratory monitoring should include a baseline pregnancy test in all female patients and a complete blood count, lipid profile, and hepatic profile in all patients. Serial follow-up of laboratory tests should be conducted every one to two weeks until stable and thereafter at intervals as clinically indicated. Cyclosporine and Mycophenolate Mofetil The immunosuppressant cyclosporine (see Chapter 53: Immunomodulators: Immunosuppressive Agents, Tolerogens, and Immunostimulants), derived from the fungus Beauveria nivea, is highly effective in the treatment of psoriasis (Ellis et al., 1991). Cyclosporine inhibits the phosphatase calcineurin and transcription of the IL-2 gene in T cells (Schreiber and Crabtree, 1992, Rao, 1994). It also inhibits antigen presentation by Langerhans' cells and degranulation of mast cells (Dupuy et al., 1991; Triggiani et al., 1989), which contribute to the pathogenesis of psoriasis. Hypertension and renal dysfunction are major concerns associated with the use of cyclosporine. The risk of developing these problems is markedly reduced by keeping the daily dosage less than 5 mg/kg and by rotating therapy periodically (Shupack et al., 1997). Hematological indices and renal function must be carefully monitored. Patients on long-term systemic immune suppression also may develop increased numbers of nonmelanoma skin cancer (Cockburn and Krupp, 1989). Mycophenolate mofetil (CELLCEPT; see Chapter 53: Immunomodulators: Immunosuppressive Agents, Tolerogens, and Immunostimulants) is another effective immune suppressant with a utility very similar to that of cyclosporine (Kitchin et al., 1997). Usual doses range from 1 to 2 g per day. Common side effects include gastrointestinal intolerance, as manifested by diarrhea, nausea, vomiting, abdominal cramping, and bone marrow suppression. Notably, the problems of hypertension and renal dysfunction seen with cyclosporine are not associated with mycophenolate mofetil. As is typical with immunosuppressants, hematological monitoring and close clinical follow-up are required. Photochemotherapy Electromagnetic radiation is a form of energy defined by its wavelength; it has been classified into different regions, as shown in Figure 65–4. Dermatologists are most concerned with the regions of ultraviolet radiation (UVC, 100 to 290 nm; UVB, 290 to 320 nm; and UVA, 320 to 400 nm) and with visible radiation (400 to 800 nm). UVC is absorbed by the ozone layer and does not reach the earth's surface. UVB, the most erythrogenic and melanogenic type of radiation, causes sunburn, suntan, skin cancer, and photoaging. The longer wavelengths of UVA are 1000-times less erythrogenic than UVB; however, they penetrate more deeply and contribute to photoaging and photosensitivity diseases. They also enhance UVB-induced erythema and increase the risk of UVC-induced carcinogenesis. Visible radiation is responsible for occasional photosensitive eruptions.
Figure 65–4. The Electromagnetic Spectrum. Solar radiation is defined in terms of wavelength. Ultraviolet and visible radiation (enlarged) are used therapeutically in dermatology; UVB for phototherapy, UVA for photochemotherapy (PUVA, psoralens plus UVA), and visible light for photodynamic therapy. Despite its side effects, nonionizing electromagnetic radiation is employed therapeutically. Phototherapy and photochemotherapy are treatment methods in which radiation of an appropriate wavelength is used to induce a therapeutic response in the absence and presence, respectively, of a photosensitizing drug. The radiation must be absorbed by a target molecule —a chromophore—which is an endogenous molecule in phototherapy and an exogenous drug in photochemotherapy. Patients should not be taking any extraneous photosensitizing medications prior to initiation of therapy. Common photosensitizing medications include, but are not limited to, phenothiazines, thiazides, sulfonamides, nonsteroidal antiinflammatory agents, sulfonylureas, tetracyclines, and benzodiazepines. PUVA: Psoralens and UVA History Photochemotherapy with psoralen-containing plant extracts was employed in Egypt and India in 1500 B.C. for the treatment of vitiligo. El Mofty at the University of Cairo first used a purified psoralen for the treatment of vitiligo in 1947. In 1974, Parrish et al. reported successful treatment of severe psoriasis with 8-methoxypsoralen (P) and UVA, and coined the acronym PUVA. PUVA has been approved for the treatment of vitiligo and psoriasis. Its widespread use with extensive follow-up has provided comprehensive data on toxicity and efficacy. Chemistry Psoralens belong to the furocoumarin class of compounds, which are derived from the fusion of a furan with a coumarin. They occur naturally in many plants, including limes, lemons, figs, and parsnips. Two psoralens, 8-methoxypsoralen (methoxsalen) and 4,5,8- trimethylpsoralen (trioxsalen;TRISORALEN) are available in the United States. Methoxsalen is used primarily due to its superior absorption. Structures of the two psoralens are shown below.