Epidermis.

The epidermis is the outermost layer of the skin and is composed almost entirely of closely packed cells. As indicated in Figure 105–1B, 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. By a process that is not fully understood, 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. Following its synthesis within melanocytes, melanin is transferred to other cells of the epidermis. Melanin protects the skin against ultraviolet 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. 105–1A).

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.

Actions and uses.

Topical glucocorticoids are employed to relieve inflammation and itching associated with a variety of dermatologic conditions (eg, insect bites, minor burns, seborrheic dermatitis, psoriasis, eczema, pemphigus). The mechanisms by which glucocorticoids suppress inflammation and other symptoms are discussed in Chapter 72.

The vehicle in which a glucocorticoid is dispersed (eg, cream, ointment, gel) can enhance the therapeutic response. How? 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 105–1, these drugs can be assigned to four groups that range in potency from low to super high. Preparations within each group are equipotent.

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 (scalp, axilla, face, eyelids, neck, perineum, genitalia) and lower from regions where penetrability is poor (back, 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 of adverse effects include use of a high-potency glucocorticoid, use of an occlusive dressing, prolonged therapy, and application over a large area.

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.

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% to 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, and systemic toxicity (salicylism) can result. Symptoms include tinnitus, hyperpnea, and psychologic disturbances. Systemic effects can be minimized by avoiding prolonged use of high concentrations over large areas.

Sulfur.

Sulfur promotes peeling and drying. The compound has been used to treat acne, dandruff, psoriasis, and seborrheic dermatitis. Sulfur is available in lotions, gels, and shampoos. Concentrations range from 2% to 10%.

Benzoyl peroxide.

Benzoyl peroxide is a first-line drug for mild to moderate acne. 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). In one study, topical benzoyl peroxide was at least as effective as oral minocycline.

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, 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 (eg, burning, blistering, scaling, swelling), the frequency of application should be reduced.

Some formulations contain sulfites, which can cause potentially serious allergic reactions. The incidence is highest in patients with asthma. Otherwise, the incidence is low.

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.

Tretinoin.

Tretinoin [Atralin, Avita, Retin-A, Retin-A Micro, Renova], a 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 below).

Actions and use.

Isotretinoin [Accutane, Amnesteem, Claravis, Sotret], a derivative of vitamin A, is used to treat severe nodulocystic acne vulgaris, a condition for which this drug is highly effective. For most patients, a single course of therapy can produce complete and prolonged remission. Because isotretinoin can cause serious side effects, use is restricted to patients with severe, disfiguring acne that has not responded to more conventional agents, including oral antibiotics. Isotretinoin is highly teratogenic, and hence must not be used during pregnancy.

Isotretinoin has several actions that may contribute to antiacne effects. The drug decreases sebum production, sebaceous gland size, inflammation, and keratinization. In addition, by decreasing availability of sebum, a nutrient for P. acnes, isotretinoin lowers the skin population of this microbe.

Adverse effects. 

Drug interactions.

Adverse effects of isotretinoin can be increased by tetracyclines and vitamin A. Tetracyclines increase the risk of pseudotumor cerebri and papilledema. Vitamin A, a close relative of isotretinoin, can produce generalized intensification of isotretinoin toxicity. Because of the potential for increased toxicity, tetracyclines and vitamin A supplements should be discontinued prior to isotretinoin therapy.

Contraindication: pregnancy.

Isotretinoin is teratogenic and must not be used during pregnancy. The drug is classified in Food and Drug Administration (FDA) Pregnancy Risk Category X: The risks of use during pregnancy clearly outweigh any possible benefits. Major fetal abnormalities that have occurred include hydrocephalus, microcephaly, facial malformation, cleft palate, cardiovascular defects, and abnormal formation of the outer ear.

IPLEDGE program.

iPLEDGE is the name of a very strict risk management program designed to ensure that no woman starting isotretinoin is pregnant and that no woman taking isotretinoin becomes pregnant. The iPLEDGE program, which went into effect December 31, 2005, replaced S.M.A.R.T. (System to Manage Accutane-Related Teratogenicity) and all other programs designed to guard against use of isotretinoin during pregnancy. The principal difference between iPLEDGE and S.M.A.R.T. is that, under iPLEDGE, all transactions involving isotretinoin must be processed through a central automated system, which tracks and verifies critical elements that control access to the drug. The program has rules that apply to the prescriber, patient, pharmacist, and wholesaler. Details regarding iPLEDGE are available online at www.ipledgeprogram.com.

Oral contraceptives.

Three combination oral contraceptives (OCs)—Estrostep, Ortho Tri-Cyclen, and YAZ—are approved for managing acne in women. Treatment is limited to females at least 15 years old who want contraception, have reached menarche, and have not responded to topical drugs. Acne may take 6 or more months to improve. Benefits are due primarily to the estrogen in combination OCs—not the progestin. Two mechanisms are involved: suppression of ovarian androgen production, and increased production of sex hormone–binding globulin, a protein that binds androgens and thereby renders them inactive. By decreasing androgen availability, estrogens decrease production of sebum. Although only three OCs are approved for acne, all estrogen-containing OCs should work. Accordingly, selection among them should be based primarily on tolerability.

Spironolactone.

Spironolactone [Aldactone] blocks a variety of steroid receptors, including those for aldosterone and sex hormones. Blockade of aldosterone receptors underlies the drug’s use as a diuretic (see Chapter 41) as well as its use in heart failure (see Chapter 48). Blockade of androgen receptors underlies benefits in females with acne. As a rule, spironolactone is added to the regimen after an oral contraceptive has proved inadequate. This sequence makes sense. Why? Because spironolactone is teratogenic, and hence contraception should be implemented before taking the drug. Adverse effects include menstrual irregularities, breast tenderness, and hyperkalemia.