Epidermis
The epidermis is the outermost layer of the skin and is composed almost entirely of closely packed cells. As indicated in Fig. 85.1B, the epidermis itself consists of several layers. The deepest, known as the basal layer or stratum germinativum, contains the only epidermal cells that are mitotically active. All cells of the epidermis arise from this layer. Production of new cells within the basal layer pushes older cells outward. During their migration, these cells become smaller and flatter. As epidermal cells near the surface of the skin, they die and their cytoplasm is converted to keratin, a hard, proteinaceous material. Because of its high content of keratin, the outer layer of the epidermis has a rough, horny texture. Because of its texture, this layer is referred to as the cornified layer or stratum corneum. The surface of the stratum corneum undergoes continuous exfoliation (shedding). This shedding completes the epidermal growth cycle.
In addition to germinal cells, the basal layer of the epidermis contains melanocytes. These cells, which are few in number, produce melanin, the pigment that determines skin color. After its synthesis within melanocytes, melanin is transferred to other cells of the epidermis. Melanin protects the skin against ultraviolet (UV) radiation, which is the principal stimulus for melanin production.
Dermis
The dermis underlies the epidermis and is composed largely of connective tissue, primarily collagen. A major function of the dermis is to provide support and nourishment for the epidermis. Structures found in the dermis include blood vessels, nerves, and muscle. The dermis also contains sweat glands, sebaceous glands, and hair follicles. Sebaceous glands secrete an oily composite known as sebum. Almost all sebaceous glands are associated with hair follicles (see Fig. 85.1A).
Subcutaneous Tissue
Subcutaneous tissue consists largely of fat. This fatty layer provides protection and insulation. In addition, the stored fat constitutes a reserve source of calories.
Topical Drug Formulations
Topical drugs are provided through a number of vehicles. The most popular are ointments, creams, lotions, gels, foams, powders, and pastes.
Ointments are thick, greasy preparations with an oil or petroleum jelly base and little, if any, water. They provide the highest medication absorption of all formulations. The enhanced penetration makes it especially useful in management of conditions with thickened skin (e.g., with lichenification secondary to prolonged scratching) or inflamed skin. Because it provides an occlusive film that retains moisture, it is not a good choice for weeping or oozing skin conditions or in areas prone to heavy perspiration. It is often an excellent choice, however, for dry skin conditions.
Creams are an oil and water emulsion. Some contain more oil than water, whereas others contain more water than oil. This affects the thickness of their consistency and how oily or sticky they feel on the skin. They are not as thick as ointments, but they are thicker than lotions. Creams tend to be good for inflamed skin and dry sensitive skin. It may or may not be useful for oozing lesions depending on the ratio of water to oil. Creams tend to be more appropriate than ointments for intertriginous areas.
Lotions are water based. Some may contain alcohol or acids, which can cause a burning sensation. They have little, if any, oil; as a result, they have a lighter feel than creams. Lotions are nongreasy, which tends to promote more patient satisfaction. Another advantage of lotions is that they are easy to spread, which makes them a good choice for large areas or for hairy areas. They are suitable for intertriginous areas. Unlike ointments and creams, they are suitable for oily skin and may even decrease oiliness depending on the ingredients.
Gels are transparent preparations that usually contain cellulose with a water or alcohol base. They liquefy on skin contact and often have a cooling effect as they dry. Because they are nongreasy and tend to have drying effects, gels are good choices for oily skin. They spread easily, so they are good for covering large or hairy areas. Because they dry clear and invisible, they may be more acceptable for facial regions. These may cause burning, but when this occurs, it is often the fault of the inactive ingredients rather than the medication.
Foams are aerated solutions. They spread easily, dry quickly, and leave negligible residue. They tend to be good choices for oily skin and large or hairy areas.
Most powders have a talc or cornstarch base. They are dry with a silky feel that reduces friction between surfaces. This can make them useful between skin folds. The dryness of the vehicle can be helpful when applied to regions that tend to perspire, such as the feet or axillae.
Pastes are mixtures of an ointment and a powder. The addition of a powder increases adherence to the skin. Because the powder disrupts the occlusive nature of an ointment, allowing for air to reach the covered skin, most pastes can be used safely in areas that are occluded, such as use of Desitin diaper rash paste beneath a diaper.
Topical Glucocorticoids
The basic pharmacology of the glucocorticoids is discussed in Chapter 56. Consideration here is limited to their use for skin disorders.
Actions and Uses
Topical glucocorticoids are employed to relieve inflammation and itching associated with a variety of dermatologic conditions (e.g., insect bites, dermatitis, psoriasis, eczema, pemphigus).
The vehicle in which a glucocorticoid is dispersed (e.g., cream, ointment, gel) can enhance the therapeutic response by helping the glucocorticoid penetrate to its site of action. The vehicle may provide additional benefits by acting as a drying agent or an emollient.
Relative Potency
Glucocorticoid preparations vary widely in potency. As indicated in Table 85.1, these drugs can be assigned to groups that range in potency from low to super high. Preparations within each group are equipotent.
TABLE 85.1
Relative Potency of Topical Glucocorticoids
| Potency Class and Drug | Formulation | Concentration |
| SUPER-HIGH POTENCY | ||
| Betamethasone dipropionate [Diprolene] | Ointment, lotion, gel | 0.05% |
| Clobetasol propionate [Clobex, Cormax, Temovate] | Cream, ointment, gel, spray, foam, lotion, shampoo | 0.05% |
| Diflorasone diacetate ointment [Psorcon] | Ointment | 0.05% |
| Fluocinonide [Vanos] | Cream | 0.1% |
| Flurandrenolide [Cordran tape] | Tape | 4 mcg/m2 |
| Halobetasol propionate [Ultravate] | Cream, ointment | 0.05% |
| HIGH POTENCY | ||
| Amcinonide [Cyclocort] | Cream, ointment, lotion | 0.1% |
| Betamethasone dipropionate [Diprolene, Diprolene AF] | Cream, ointment, lotion | 0.05% |
| Desoximetasone [Topicort] | Cream, ointment, gel, spray | 0.5%, 0.25% |
| Diflorasone diacetate cream [ApexiCon, Florone, Maxiflor, Psorcon] | Cream | 0.05% |
| Fluocinonide [Fluonex, Lidex, Vanos] | Cream, ointment, gel, solution | 0.05% |
| Halcinonide [Halog] | Cream, ointment | 0.1% |
| Triamcinolone acetonide | Ointment | 0.5% |
| MEDIUM TO HIGH POTENCY | ||
| Amcinonide cream [Cyclocort] | Cream | 0.1% |
| Betamethasone dipropionate cream [Diprosone] | Cream | 0.05% |
| Diflorasone diacetate [ApexiCon, Psorcon] | Cream, ointment | 0.05% |
| Fluocinonide emollient cream [Lidex E] | Cream | 0.05% |
| Fluticasone propionate ointment [Cutivate] | Ointment | 0.005% |
| Triamcinolone acetonide ointment [Aristocort A] | Ointment | 0.01% |
| Triamcinolone high-potency cream [Aristocort-HP] | Cream | 0.05% |
| MEDIUM POTENCY | ||
| Betamethasone dipropionate | Lotion | 0.05% |
| Betamethasone valerate [Beta-Val, Luxiq, Valisone] | Cream, ointment, lotion, foam | 0.1%, 0.12% |
| Clocortolone pivalate [Cloderm] | Cream | 0.1% |
| Desoximetasone [Topicort LP] | Cream, ointment, gel, spray | 0.05% |
| Fluocinolone acetonide [Synalar] | Cream, ointment | 0.025%, 0.2% |
| Flurandrenolide [Cordran, Cordran SP] | Cream, lotion | 0.05% |
| Fluticasone propionate [Cutivate] | Cream | 0.05% |
| Hydrocortisone butyrate [Locoid, Locoid Lipocream] | Cream, ointment, lotion, solution | 0.1% |
| Hydrocortisone valerate [Westcort] | Cream, ointment | 0.2% |
| Mometasone furoate [Elocon] | Cream, ointment, lotion, solution | 0.1% |
| Prednicarbate [Dermatop] | Cream, ointment | 0.1% |
| Triamcinolone acetonide [Kenalog] | Cream, lotion | 0.1% |
| Ointment | 0.025% | |
| Aerosol | 0.2% | |
| LOW POTENCY | ||
| Alclometasone dipropionate [Aclovate] | Cream, ointment | 0.05% |
| Desonide [DesOwen, LoKara, Verdeso] | Cream, ointment, gel, lotion, foam | 0.05% |
| Fluocinolone acetonide [Capex, Synalar] | Cream, oil, shampoo, solution | 0.01% |
| Hydrocortisone acetate [Lanacort 10, U-Cort] | Cream, ointment | 1% |
| Hydrocortisone butyrate [Locoid] | Cream, ointment, lotion, solution | 0.1% |
| Triamcinolone acetonide [Kenalog] | Cream, ointment, lotion | 0.025% |
| LEAST POTENCY | ||
| Hydrocortisone [Ala-Cort, Anusol-HC, Cortaid, Cortizone-10, Hytone] | Cream, ointment, lotion | 1%, 2.5% |
It is important to note that the intensity of the response to topical glucocorticoids depends not only on the concentration and inherent activity of the glucocorticoid but also on the vehicle employed and the method of application. Occlusive dressings can enhance percutaneous absorption by as much as 10-fold, thereby greatly increasing pharmacologic effects.
Absorption
Topical glucocorticoids can be absorbed into the systemic circulation. The extent of absorption is proportional to the duration of use and the surface area covered. Absorption is higher from regions where the skin is especially permeable (axilla, face, eyelids, neck, perineum, genitalia) and lower from regions where penetrability is poor (palms, soles). Absorption through intact skin is lower than through inflamed skin. As noted, absorption is influenced by the vehicle and can be greatly increased by an occlusive dressing.
Adverse Effects
Adverse effects may be local or systemic. Factors that increase the risk for adverse effects include use of a high-potency glucocorticoid, use of an occlusive dressing, prolonged therapy, and application over a large area.
Local Reactions
Glucocorticoids increase the risk for local infection and may also produce irritation. With prolonged use, glucocorticoids can cause atrophy of the dermis and epidermis, resulting in thinning of the skin, striae, purpura, and telangiectasis. Long-term therapy may induce acne and hypertrichosis (excessive growth of hair, especially on the face).
Systemic Toxicity
Topical glucocorticoids can be absorbed in amounts sufficient to produce systemic toxicity. Principal concerns are growth delay (in children) and adrenal suppression (in all age groups). Systemic toxicity is more likely under extreme conditions of use (prolonged therapy in which a large area is treated with big doses of a high-potency agent covered with an occlusive dressing). When these conditions are present, adrenal suppression can occur.
Administration
Topical glucocorticoids should be applied in a thin film and gently rubbed into the skin. Patients should be advised not to use occlusive dressings (bandages, plastic wraps) unless the prescriber tells them to. Tight-fitting diapers and plastic pants can act as occlusive dressings and should not be worn when glucocorticoids are applied to the diaper region of infants. The same would be true of adults who wear diapers owing to urinary or bowel incontinence.
Keratolytic Agents
Keratolytic agents are drugs that promote shedding of the horny layer of the skin. They are used to treat conditions where there is an overgrowth or abnormal thickening of the skin. Effects range from peeling to extensive desquamation of the stratum corneum. Two keratolytic compounds—salicylic acid and sulfur—are considered next. A third agent—benzoyl peroxide—is discussed later under “Topical Drugs for Acne.”
Salicylic Acid
Salicylic acid promotes desquamation by dissolving the intracellular cement that binds scales to the stratum corneum. Keratolytic effects are achieved with concentrations between 3% and 6%. At concentrations above 6%, tissue injury is likely. Low (3%–6%) concentrations are used to treat dandruff, seborrheic dermatitis, acne, and psoriasis. Higher concentrations (up to 40%) are used to remove warts and corns.
Salicylic acid is readily absorbed through the skin. Though rare, systemic salicylate toxicity (salicylism) can result when large amounts are used for a prolonged period. Symptoms of salicylism include tinnitus, hyperpnea, and psychological disturbances. Systemic effects can be minimized by avoiding prolonged use of high concentrations over large areas.
Sulfur
Sulfur promotes peeling and drying. Compounds containing sulfur have been used to treat acne, dandruff, psoriasis, and seborrheic dermatitis. Sulfur is available in lotions, gels, and shampoos. It is commonly combined with salicylic acid for the additive effects (e.g., Sebex shampoo). Concentrations range from 2% to 10%.
Acne
Acne is the most common dermatologic disease. About 85% of teenagers develop acne, which often persists into adulthood. Acne accounts for more visits to dermatologists than any other disorder. In the United States the direct costs of acne exceed $1 billion a year, including about $100 million spent on acne products sold over the counter.
Pathophysiology
Acne is a chronic skin disorder that usually begins during puberty. The disease is more common and more severe in males. Lesions typically develop on the face, neck, chest, shoulders, and back. In mild acne, open comedones (blackheads) are the most common lesion. A comedo forms when sebum combines with keratin to create a plug within a pore (oxidation of the sebum causes the exposed surface of the plug to turn black). Closed comedones (whiteheads) develop when pores become blocked with sebum and scales below the skin surface. In its most severe form, acne is characterized by abscesses and inflammatory cysts. As a rule, acne begins to improve after puberty and, for some, clears entirely during the early 20s. However, with some people, the disease continues for decades.
Onset of acne is initiated by increased production of androgens during adolescence. Under the influence of androgens, sebum production and turnover of follicular epithelial cells are increased, leading to plugging of pores. Symptoms are intensified by the activity of Propionibacterium acnes, a microbe that converts sebum into irritant fatty acids. This bacterium also releases chemotactic factors that promote inflammation. Oily skin and a genetic predisposition also contribute.
Overview of Treatment
Because acne is a chronic disease, treatment is prolonged. Fortunately, almost all patients respond well. Effective treatment will prevent scarring and limit the duration of symptomatic disease and will thereby minimize the psychological effect of acne.
Nonpharmacologic Therapy
Nonpharmacologic measures can help minimize acne lesions, especially in patients with milder acne. Surface oiliness should be reduced by cleansing with a gentle nonirritant soap a couple of times a day. Care should be taken to avoid irritation from vigorous scrubbing or use of abrasives. Oil-based make-up or moisturizing products should not be used. Additional measures (e.g., comedo extraction, dermabrasion) may be indicated for some individuals. Research has demonstrated that dietary changes provide no benefit.
Drug Therapy
Drugs for acne fall into two major groups: topical drugs and oral drugs (Table 85.2). The topical drugs have two principal subgroups: antibiotics and retinoids. Likewise, the oral drugs have two principal subgroups: antibiotics and retinoids. Occasionally, other agents, such as keratolytic agents (e.g., salicylic or azelaic acid) or hormonal agents (e.g., oral contraceptives [OCs]) may be used.
TABLE 85.2
Drugs for Acne
| TOPICAL DRUGS | |
| Antibiotics | |
| Retinoids | |
| Retinoid/antibiotic combinations | |
| Others | |
| ORAL DRUGS | |
| Antibiotics | |
| Retinoids | |
| Hormonal agents | |
]
]Drug selection is based on symptom severity. For patients with relatively mild symptoms, topical therapy can suffice. When symptoms are more severe, oral therapy is required. Mild acne can be managed with topical antibiotics and topical retinoids. Moderate acne can be treated with oral antibiotics (e.g., doxycycline, minocycline) and comedolytics (retinoids and azelaic acid). In addition, hormonal agents—combination OCs and spironolactone—can be used in young women whose acne is unresponsive to other drugs. The principal agent for severe acne is isotretinoin.
Topical Drugs for Acne
Antibiotics
Benzoyl Peroxide
Benzoyl peroxide, a first-line drug for mild to moderate acne, is both an antibiotic and keratolytic. Improvement can be seen within days of starting treatment. Benefits derive primarily from suppressing growth of P. acnes. The presumed mechanism is release of active oxygen. In addition to suppressing P. acnes, benzoyl peroxide can reduce inflammation and promote keratolysis (peeling of the horny layer of the epidermis).
Unlike other topical antimicrobials, benzoyl peroxide does not promote emergence of resistant P. acnes. In fact, the drug is often combined with clindamycin or erythromycin to protect against resistance to those drugs, which can occur when those antibiotics are used alone.
Benzoyl peroxide may produce drying and peeling of the skin. If signs of severe local irritation occur (e.g., burning, blistering, scaling, swelling), the frequency of application should be reduced. Benzoyl peroxide has been associated with potentially serious hypersensitivity reactions, especially in patients with asthma. In Canada, 131 instances of severe allergies experienced by patients using benzoyl peroxide and/or salicylic acid prompted a safety review. In December, 2015, Health Canada issued a public warning. A revised drug monographs will include information on sensitivity testing. (See http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/56268a-eng.php.)
Benzoyl peroxide is available in a variety of formulations (e.g., lotion, cream, gel, foam). Concentrations range from 2.5% to 10%. For initial therapy, once-daily application is recommended. Over time, the frequency of administration can be increased (to a maximum of 3 times a day) as tolerance permits. Patients should be advised to keep the drug away from the eyes, mouth, and mucous membranes as well as inflamed or denuded skin.
Clindamycin and Erythromycin
Like benzoyl peroxide, topical clindamycin [Cleocin, others] and erythromycin [Eryderm, others] suppress growth of P. acnes. In addition, these drugs can decrease inflammation. Monotherapy with either drug quickly leads to resistance. To protect against emergence of resistance, these drugs can be combined with benzoyl peroxide. Two fixed-dose combinations are available: clindamycin/benzoyl peroxide, sold as BenzaClin and Clindoxyl 
; and erythromycin/benzoyl peroxide, sold as Benzamycin.
Dapsone
Dapsone [Aczone] has been used for oral therapy of leprosy for decades. In patients with acne, the drug yields a modest decrease in inflammation and number of lesions. The mechanism of action underlying antiacne benefits has not been established. Dapsone is available as a 5% gel in 30-, 60-, and 90-g tubes for twice-daily application. The site should be washed and dried before applying the drug, and the hands should be washed afterward. The most common side effects of dapsone gel are oiliness, peeling, dryness, and erythema. These effects are caused primarily by the gel vehicle, and not by dapsone. Oral dapsone, but not topical dapsone, poses a risk for hemolytic anemia and peripheral neuropathy. Combining dapsone with benzoyl peroxide can turn the skin yellow or orange. Until more is known, dapsone should be reserved for patients who can’t tolerate traditional topical treatments.
Retinoids
The topical retinoids—derivatives of vitamin A (retinol)—are a cornerstone of acne therapy. These drugs can unplug existing comedones and prevent development of new ones. In addition, they can reduce inflammation and improve penetration of other topical agents. Topical retinoids currently approved for acne use are tretinoin, adapalene, and tazarotene. They may be used alone or in combination with other drugs, including topical and oral antimicrobials.
Tretinoin
Tretinoin, a topical derivative of vitamin A, is used for acne and to remove fine wrinkles. Formulations for acne are marketed as Atralin, Avita, Retin-A, and Retin-A Micro. The formulation for wrinkles, which is nearly identical to one of the formulations for acne, is marketed as Renova. Tretinoin should not be confused with isotretinoin, a powerful oral antiacne medicine (see later discussion).
Use for Acne.
Tretinoin is approved for topical treatment of mild to moderate acne. Benefits derive from normalizing hyperproliferation of epithelial cells within hair follicles. Tretinoin also causes thinning of the stratum corneum and can thereby facilitate penetration of other drugs. Therapeutic effects can be enhanced by combining tretinoin with benzoyl peroxide, topical antibiotics, and oral antibiotics.
Use for Fine Wrinkles.
Tretinoin is approved for reducing fine wrinkles, tactile roughness, and mottled hyperpigmentation (“liver spots,” age spots) in facial skin. Benefits may derive from suppressing genes that code for specific proteases that break down collagen and elastin. In clinical trials, responses to tretinoin were modest. In fact, many patients achieved equivalent effects with a program of comprehensive skin care and sun protection. It is important to appreciate that tretinoin does not repair deep, coarse wrinkles and other damage caused by chronic sun exposure. Furthermore, the drug does not reverse photoaging or restore the microscopic structure of skin to a more youthful pattern. Benefits in patients older than 50 years have not been established.
Adverse Effects.
Tretinoin can cause localized reactions, but absorption is insufficient to cause systemic toxicity. In patients with sensitive skin, tretinoin may induce blistering, peeling, crusting, burning, and edema. These effects can be intensified by concurrent use of abrasive soaps and keratolytic agents (e.g., sulfur, resorcinol, benzoyl peroxide, salicylic acid). Accordingly, these preparations should be discontinued before beginning tretinoin therapy. Skin reactions with two formulations—Avita and Retin-A Micro—may be less intense than those caused by Retin-A, an older formulation.
Tretinoin increases susceptibility to sunburn. Patients should be warned to apply a sunscreen with a sun protection factor (SPF) of 15 or greater and wear protective clothing. Patients with existing sunburn should not apply the drug.
Preparations, Dosage, and Administration.
For treatment of acne, tretinoin is available under four trade names: Retin-A, Retin-A Micro, Atralin, and Avita. Products marketed as Retin-A are available in two formulations: cream (0.025%, 0.05%, and 0.1%) and gel (0.01% and 0.025%). Retin-A Micro is supplied as a gel (0.04% and 0.1%), Atralin as a 0.05% gel, and Avita as a 0.025% cream or gel. All products are administered topically, usually once a day at bedtime. Before application, the skin should be washed, toweled dry, and allowed to dry fully for 20 to 30 minutes. Tretinoin should not be applied to open wounds or to areas of sunburn or windburn. Contact with the eyes, nose, ears, and mouth should be avoided.
For fine wrinkles of the face, tretinoin is available in a 0.02% cream, sold as Renova. Application is done once daily at bedtime. Cosmetics should be washed off before use. Up to 6 months of treatment may be needed to see a response, and treatment must continue to maintain the response.
Adapalene
Adapalene [Differin] is a topical antiacne drug similar to tretinoin. Through actions in the cell nucleus, adapalene modulates inflammation, epithelial keratinization, and differentiation of follicular cells. As a result, the drug reduces formation of comedones and inflammatory lesions. Benefits take 8 to 12 weeks to develop. During the early weeks, adapalene may appear to exacerbate acne by affecting previously invisible lesions. In clinical trials, 0.1% adapalene gel was as effective as 0.025% tretinoin gel in reducing the total number of comedones, and it was more effective than tretinoin in reducing the total number of acne lesions and inflammatory lesions.
Adverse effects are limited to sites of application. The drug is not absorbed in quantifiable amounts, so systemic effects are absent. Common side effects include burning, pruritus or burning immediately after application, erythema, dryness, and scaling. These are most likely during the first 2 to 4 weeks of treatment and tend to subside as treatment continues.
Adapalene increases the risk for developing sunburn and can intensify existing sunburn. Accordingly, all patients should apply a sunscreen and wear protective clothing. In addition, adapalene should not be used until existing sunburn has resolved.
Adapalene, by itself, is available in three 0.1% and 0.3% formulations—gel, cream, and lotion—for once-daily application in the evening. In addition, adapalene is available in a fixed-dose combination with benzoyl peroxide. Contact with the eyes, lips, angles of the nose, and mucous membranes should be avoided. It is also important to avoid contact with abraded, sunburned, or eczematous skin.
Tazarotene
Tazarotene [Avage, Tazorac] is indicated for topical therapy of acne, wrinkles, and psoriasis. Like tretinoin and adapalene, tazarotene is a derivative of vitamin A. For treatment of acne, tazarotene is available in a gel (0.05%, 0.1%) and cream (0.05%, 0.1%). The gel or cream is applied to affected areas of the face each evening. The face should be cleaned and dried before application. The most common side effects—itching, burning, and dry skin—occur more often with tazarotene than with tretinoin or adapalene. Like other retinoids, tazarotene sensitizes the skin to UV light, and hence patients should be advised to use a sunscreen and wear protective clothing.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
