Epidermis

The epidermis, or thin outer skin layer, has no direct blood supply of its own; it is nourished only by diffusion. It consists of four layers of epithelial cells (see Figure 48-1):

Figure 48-1 Structures of the skin.

Note: Details of nerves (autonomic and sensory) and sensory nerve endings are not shown.

Melanocytes, which are responsible for synthesising melanin, a pigment that occurs naturally in the hair and skin, are also located deep in the stratum germinativum. The more melanin that is present, the deeper brown the skin colour. Melanin is a protective agent: it blocks ultraviolet rays, thus preventing injury to the underlying dermis and tissues.

Dermis

The dermis lies between the epidermis and subcutaneous fat. It is about 40 times thicker than the epidermis and contains elastic and connective tissues that provide support for its blood vessels, nerves, lymphatic tissue, sweat glands, sebaceous glands and hair follicles.

Below the dermis is the hypodermis, or subcutaneous layer, which contributes flexibility to the skin. Subcutaneous fat tissue is an area for thermal insulation, nutrition and cushioning or padding.

The skin contains three types of exocrine glands opening on the surface of the skin through ducts in the epithelium: sebaceous (producing lubricating sebum), eccrine (producing sweat and helping cooling) and apocrine (producing odoriferous compounds). Normal skin pH is 4.5–5.5, which is weakly acidic and hence has a protective and antiseptic function. The appendages of the skin are the hair and nails.

Functions of the skin

The skin serves many functions in the body; some of the major functions are listed here.

Causes of skin disorders

Disorders of the skin may be due to allergy, infection, sensitivity to drugs or other chemicals, emotional stress, genetic predisposition (e.g. atopic eczema or psoriasis), hormonal imbalances or degenerative disease. Sometimes the cause of the skin disorder is unknown and the treatment is empirical, in the hope that the right remedy will be found; corticosteroids are often used in skin disorders for their anti-inflammatory and immunosuppressant actions.

Signs and symptoms

Common dermatological disorders include acne vulgaris (cystic acne and acne scars), atopic dermatitis, eczema, folliculitis, fungal infections, herpes simplex, lichen simplex, psoriasis, seborrhoeic dermatitis, skin cancers, verrucae (warts) and vitiligo. Reactions or disorders of the skin are manifested by symptoms such as itching, pain or tingling and by signs such as swelling, redness, papules, pustules, blisters and hives.

Dermatological diagnosis may require physical assessment; personal and family medical history; drug history including over-the-counter (OTC) medications; and laboratory tests, cytodiagnosis and biopsy. When the nature of the lesion has been established, its characteristics should be defined according to size, shape, surface and colour (Figure 48-2) and distribution on the body.

Figure 48-2 Different types of skin lesions and some conditions associated with them. Bulla: large vesicle containing serous fluid (examples: blister; pemphigus vulgaris). Cyst: elevated encapsulated cavity lined by epithelium; filled with liquid or semisolid material (example: sebaceous cyst). Lichenification: rough, thickened epidermis; accentuated skin markings due to rubbing or irritation (example: chronic dermatitis). Macule: flat; non-palpable; discoloured lesion, brown, red, purple or white (examples: freckle; flat mole; rubella; rubeola). Nodule: small collection of tissue, elevated; circumscribed; palpable; 1–2 cm in diameter (examples: erythema nodosum; lipoma). Papule: elevated; palpable; circumscribed; less than 1 cm in diameter (examples: wart; drug-related eruption; pigmented naevus; eczema). Plaque: elevated; flat-topped; solid; rough; superficial papule greater than 1 cm in diameter (examples: psoriasis; eczema). Pustule: visible collection of pus within or beneath epidermis; vesicle filled with purulent fluid (examples: impetigo; acne). Scale: irregular, thin, compacted flaky keratinised cells; dry or oily; varied size; silver, white, or tan (examples: psoriasis; exfoliative dermatitis). Tumour: elevated swelling; may or may not be clearly demarcated or differ in skin colour; growth is uncontrolled (examples: basal cell carcinoma; malignant melanoma). Vesicle: small, elevated, circumscribed, superficial sac filled with serous fluid; (examples: blister; varicella). Wheal, hives: smooth, slightly elevated, irregular-shaped area of oedema; solid, transient, often itchy (examples: urticaria; insect bite).

Source: Beare & Myers 1998; Dorland 2003.

Skin conditions vary over time. Acute conditions tend to show red, burning, blistered or weeping skin (such as from burns); thick ointments cannot be applied to these lesions, which are best treated with lotions that cool by evaporation. Subacute conditions may be oedematous, hot and chapped; creams and gels can be applied. Chronic skin conditions tend to be scaling, lichenified, crusting and dry; moisturising creams and ointments may soften such skin.

How much to prescribe?

How much of a topical preparation is needed for one dose? This is less easy to estimate than the quantity of tablets or other solid dose forms. Current guidelines suggest that for a cream or ointment to cover an adult’s face and neck would require about 1.25 g for one application, so twice-daily application for 10 days would require a 25–30 g tube of cream. Another way to calculate is to follow the guidelines of the Australian Medicines Handbook, where it is suggested, for example, that for a 3–5-year-old child, twice-a-day application of a topical ointment for 1 week would require 10 g for the face and neck, 15 g for arm and hand, 20 g for leg and foot etc. Some creams are provided in a tube with dose advised by mm or cm of cream squeezed out; other prescribers might recommend ‘enough to cover a 10 cent coin’ or similar suggestion.

Hydration of skin

Keratin in the outer skin layer provides a waterproof barrier; to enhance drug absorption the epidermis needs to be hydrated. Some medications are therefore applied then covered with an occlusive dressing (such as plastic wrap, rubber gloves or shower cap; see Figure 48-3 later) or administered in an occlusive type of ointment (e.g. zinc cream or petroleum jelly) because both will trap and prevent water loss (sweat) from the skin, thus increasing epidermis hydration.

Figure 48-3 Examples of occlusive dressing to enhance hydration of particular areas of skin and transcutaneous absorption of drugs. A Plastic wrap applied to upper trunk. B Plastic wrap applied to foot. C Rubber glove applied to hand and sealed around wrist.

Skin layers to be crossed

For transcutaneous absorption (aka percutaneous absorption) of drugs into the bloodstream, the layers of skin cells and membranes through which drugs must pass are:

Nicotine, hyoscine, oestrogens, fentanyl and glyceryl trinitrate are formulated in ointments or patches for transdermal absorption. Chemicals can also be absorbed unintentionally across the skin, with unexpected consequences (see case history in Clinical Interest Box 48-1).

Factors affecting transcutaneous absorption

Absorption through the skin is slow, incomplete and variable (except for lipid-soluble agents). The extent of absorption depends on:

Larger molecules and more water-soluble drugs can have their permeation through the skin enhanced by physical methods such as iontophoresis, ultrasound and skin abrasion.

Vehicles and emulsions

The drug is dissolved or mixed into a vehicle, i.e. the liquid or solid which carries the drug to the site of application on the skin. Many formulations are emulsions (liquid or semi-solid mixtures of an aqueous phase and an oily phase, with one phase distributed as tiny droplets in the other).¹ A lipid-soluble drug such as oestradiol, nicotine or glyceryl trinitrate will distribute into the oily phase of an emulsion, whereas a water-soluble drug (diphen hydramine, lignocaine) will distribute into the aqueous phase. Microemulsions, with nanoparticle-sized droplets, are being formulated to increase markedly the surface area for delivery of the drug to the skin.

Wet or dry preparations

Some topical formulations or vehicles may provide a useful effect without an active ingredient—simply rubbing in or dabbing on may have a warming or drying effect. The old saying in dermatology was ‘If it’s wet, dry it; if it’s dry, wet it’. For dry, scaly skin as found in psoriasis or dry eczema, an ointment with an occlusive emollient (softening) effect is helpful, such as lanolin or zinc cream. An area of acute inflammation that is oozing often needs a soothing evaporative lotion such as aluminium acetate solution or calamine lotion or a powder. If the skin lesion is painful, wet and located on an area rubbed by clothing, then a dusting powder such as talcum or starch may be appropriate to reduce friction and help dry the area. However, it has been shown that lesions heal better with less scarring when kept moist, so the current emphasis is on moist wound healing, e.g. under a medicated dressing (described later under ‘Treatment of pressure sores’).

Multiple ingredients

Pharmaceutical formulations for topical administration may include a wide range of ingredients, such as ointment or cream bases, water, suspending agents, emulsifying agents, preservatives, antioxidants, thickening agents, long-chain fatty acid esters and alcohols, colouring agents and perfumes, as well as the active drug. For example, one commercial ‘lip revitaliser’ contains 38 listed ingredients plus flavours! (It has been said that calamine lotion may make a lot of mess without doing a lot of good. This could be said of many old-fashioned topical preparations, which may remain in the pharmacopoeia without ever having been subjected to controlled clinical trials of safety and efficacy.)

Formulations and agents

Phototoxicity and photoallergy reactions

Ultraviolet radiation damage

Extended exposure to the sun, whether from sunbathing or as a normal consequence of an outdoor occupation or lifestyle, can lead to sunburn, premature ageing of the skin (photoageing), immunosuppression and skin disorders including cancers. The damage is caused by solar ultraviolet radiation (UVR), which comprises the part of the spectrum of electromagnetic radiation with wavelengths shorter than those of visible light (at the violet end of the colour spectrum) and longer than those of X-rays.

Absorbers or reflectors

Sunscreen preparations are applied to absorb and/or to reflect UVR, in order to reduce the risks of photo-ageing, sunburn and skin cancers. It should be noted that sunscreens may be more effective at preventing sunburn than preventing skin cancers.

Absorbing chemicals absorb and block at least 85% of the UVB. Absorbing agents are chemicals such as p-aminobenzoic acid (PABA) derivatives, benzophenones (which absorb both UVA and UVB), cinnamates, some salicylates, camphors and anthranilates (see Table 48-2).

Table 48-2 Some commercial sunscreen preparations

Physical or opaque sun blocks contain agents that reflect and scatter UVB and UVA but do not absorb it. Reflectors include chemicals such as titanium dioxide and zinc oxide. These agents are opaque (e.g. zinc creams, which look like thick white paste) and must be applied heavily to physically block out the UVR, thus they are not cosmetically acceptable to most people.

Sun protection factors

The sun protection factor (SPF) is a value given to a sunscreen preparation to indicate its effectiveness. It is largely determined by the sunscreening agents (whether chemical or physical) present in the preparation. The SPF for a product is the ratio between the exposures to UVB required to cause erythema (reddening) with and without the sunscreen. This is expressed as the MED, or the minimal erythemal dose: if a person experiences 1 MED with 25 units of UVR (in an unprotected state) and if after application of a sunscreen the person requires 250 units of radiation to produce the same amount of reddening, then this product will be given an SPF rating of 10. The higher the SPF, the longer it takes to burn or develop a tan. However, ‘SPF numbers should not be translated into burn times for individuals’ (Dermatology Expert Group 2009).

The SPF scale is a logarithmic scale rather than an arithmetic one, thus a sunscreen with SPF 2 gives a 50% reduction in UVB passage (50% penetration), SPF 4 gives 75% reduction (25% penetration) etc. Hence it can be calculated that SPF 16 (i.e. 15+) reduces UVB passage by about 94% of UVB, whereas a screen with SPF 32 (30+) reduces it by 97%. Thus, although they sound much more effective, there is little useful difference between preparations with very high SPF values. A more important consideration is the water-resistance time of the product, because this period may be much shorter than the ‘SPFallowed’ time.

Water resistance of sunscreens

The efficacy of a sunscreen agent depends on its ability to remain effective during vigorous exercise, sweating and swimming. Two categories established are ‘water-resistant’ and ‘very water-resistant’ (waterproof). Water-resistant products maintain sun protection for at least 40 minutes in water; very water-resistant products maintain sun protection for at least 80 minutes in water. Water resistance is largely dependent on the vehicle used in the product, in particular how water-soluble it is; thus oil-based lotions and creams are likely to remain on the skin longer while swimming than are O/W creams or lotions.

Application of sunscreens

Sunscreens should be liberally applied to all exposed body areas (except eyelids) and reapplied frequently to achieve the maximum effectiveness. It has been recommended that sun block be applied 30 minutes before exposure to allow adequate skin penetration, and reapplied every 2 hours depending on factors such as the product used (the SPF and water resistance category), activity and sweating levels, time of day, cloud cover and reflections. It is recommended that individuals stay out of the sun when the UVR is at the highest intensity, usually between 11 am and 3 pm, when two-thirds of the daily solar radiation occurs.

Logically, it can be seen that reapplication does not ‘allow’ another number of hours of sun—if a person has already had enough UVR to reach the MED, then any further exposure will cause more erythema, i.e. burning. Because the amount of sunscreen applied is often only one-third to half of what is necessary, the theoretical SPF is rarely achieved, which explains why people get sunburnt despite applying sunscreen. Generally, Australians do not use enough sunscreen—a family of four on a beach holiday should use a bottle of sunscreen every couple of days, but many families make a bottle last a year! Sunscreens are dated products and may lose efficacy if kept after their use-by date.

Infants should be kept out of the sun; children older than 6 months should always wear protective clothing, hats and sunscreens, with SPF 15 to SPF 30. It has been projected that consistent use of SPF 15 products from 6 months through to 18 years of age will result in about 80% reduction in the risk of skin cancer over a person’s lifetime.

Sunscreens and low vitamin D

There has been an increasing incidence of vitamin D deficiency in Australia in the last few years, causing rickets or osteomalacia (see Chapter 37). This has been explained partly by immigration of dark-skinned people who may wear long covering clothing and veils (preventing sun activation of vitamin D in the skin) and partly by increasing protection of skin from the sun by use of shade, hats and sunscreens. The prevalence is also high in institutionalised elderly people. The Dermatology Expert Group (2009) suggests that ‘fair-skinned Australians should be able to maintain adequate vitamin D concentrations with 10 minutes of sun exposure to the face, arms and hands on most days of the week during summer, and for 2–3 hours per week over winter ... Patients who receive little sunlight should be investigated for vitamin D deficiency and when present, supplemental vitamin D should be offered’.

Antiseptics

Many topical preparations are available OTC, labelled as first-aid products to help prevent infection in minor cuts, burns or injuries. These generally contain simple antiseptic or disinfectant-type products and are effective for first-aid treatment but not for specific bacterial infections. Antiseptics (skin disinfectants) are solutions or creams of antimicrobial agents applied topically to the skin; they usually contain chemicals that are very effective but too toxic to be administered internally. Many have simple detergent, solubilising actions. Examples include benza lkonium chloride, triclosan, chlorhexidine, cetrimide, povidone–iodine and hypochlorite solutions (see Appendix 2). Plant products such as aloes, benzoin and oils of melaleuca, lemon, clove, thyme and lemongrass have mild antiseptic properties.

Common adverse effects

Sensitisation to many topical antibiotics can occur. Prolonged use can produce superinfection as an overgrowth of non-susceptible organisms such as fungi. Photosensitivity is reported with topical gentamicin. Chloramphenicol used topically can cause systemic adverse effects, including bone marrow hypoplasia and blood dyscrasias, as well as local effects such as itching, burning, urticaria and vesicular and maculopapular dermatitis. Topical fusidic acid is likely to induce resistance.

Antibiotics only used topically

Aciclovir and idoxuridine

Aciclovir and idoxuridine are used for treatment of cutaneous herpes simplex infections of the lips (‘cold sores’) or genital areas. Aciclovir is activated in herpesinfected cells to a metabolite that inhibits viral DNA polymerase, thus inhibiting further viral replication. Topical aciclovir is used for the treatment of herpes simplex (non-life-threatening) in immunocompromised patients; however, systemic aciclovir is much more effective. Another guanine analogue, penciclovir, is also formulated in a lip cream for labial herpes simplex.

Idoxuridine is an antimetabolite with a mechanism of action similar to those of the antitumour antimetabolites: its structure is very similar to that of the nucleic acid base thymidine, and it inhibits the incorporation of thymidine into viral DNA and hence blocks viral replication, analogous to the antimetabolites used in cancer chemotherapy (see Figure 42-1). It is available combined with lignocaine in a cream for use in herpes simplex infections (e.g. ‘cold sores’ on the lips).

Adverse reactions from topical application of aciclovir or idoxuridine include hypersensitivity reactions, pruritus and stinging. The dosage is enough for adequate covering of the lesions with ointment, from as early as possible in the infection, every 4 hours daily for 5 days.

Treatment of warts

Although warts are caused by a virus (human papillo mavirus, HPV), they are not treated with specific antiviral drugs. Warts usually resolve without treatment, as they are overcome by the body’s immune defences. In immunocompromised patients, however, they can become extensive. Anogenital warts are predominantly transmitted in young people by sexual intercourse. The condition can undergo malignant transformation, and in women there is a strong association with cervical cancer; there is now an effective vaccine against HPV.

Treatment for warts depends largely on the site involved and extent of spread. Topical application of keratolytics, such as salicylic acid and trichloroacetic acid, and topical antimicrobials, including podophyllotoxin and glutaraldehyde, have been used. Non-pharmacological treatments include curettage, electrosurgery and cryotherapy with liquid nitrogen or solid carbon dioxide.

A new drug, imiquimod, is used for treating external genital and perianal warts; it acts via agonist activity at toll-like receptor-7 to enhance the body’s immune response. (It has also been approved for use by topical application in treatment of solar keratoses and some non-melanocytic skin cancers such as superficial basal cell carcinomas when surgical removal is not appropriate.) For anogenital warts a 5% cream is applied topically at night 3 nights per week for a maximum of 16 weeks; severe inflammatory responses are possible.

Fungal skin infections

Three pathogenic fungi (dermatophytes) that can cause superficial fungal infections (dermatophytoses) without systemic infection are Microsporum, Trichophyton and Epidermophyton; there can also be mixed infections. Systemic mycoses usually occur only in severely immunocompromised patients.

Dermatophytes exist in moist, warm environments, such as skin areas covered by shoes and socks (tinea pedis, or athlete’s foot), or in the groin, scalp or trunk. The fungi invade the stratum corneum and cause inflammation and induce sensitivity when they penetrate the epidermis and dermis.

Because the stratum corneum is shed daily, spread of the fungi occurs by contact, commonly around swimming pools or in bathrooms. General hygiene measures such as wearing sandals in communal change-rooms and showers and drying skin well, especially between the toes, help reduce infection. Before starting treatment, skin or nail scrapings should be taken for microscopic identification of the causative organism. Treatment may be required for many months, and relapse after cessation is common.

Foot infections are particularly dangerous in people with diabetes, and fungal infections can lead to bacterial infections, gangrene and amputations (see Chapter 36). Onychomycosis (fungal infection of toenails) is a significant predictor of foot ulcers, so early intervention and good foot care are critical.

Antifungals

The primary topical antifungal agents include the imidazole group (clotrimazole, ketoconazole, bifonazole, miconazole etc), terbinafine and amorolfine, and miscellaneous antifungal agents, including undecylenic, benzoic, salicylic and propionic acid products, tolnaftate, the antibiotics nystatin and griseofulvin, povidone–iodine, a new antifungal ciclopirox and a variety of antifungal combination creams, ointments, powders, sprays, liquids and paints (see Chapter 45).

Fungal infections of the nails (onychomycoses) are particularly resistant to treatment by usual topical or oral formulations, so a medicated nail varnish has been developed (Drug Monograph 48-1). See Table 48-3 for the generic names, availability status (OTC or prescription) and comments on topical antifungal products. Adverse reactions with the use of the topical antifungals are generally mild and include local irritation, pruritus, erythema and stinging.

Table 48-3 Some topical antifungal agents

Treatment of pediculosis (lice infestation)

Pediculosis is a parasite infestation of lice on the skin of a human. Lice are transmitted from one person to the next by close contact with infested people, clothing, combs and towels. There are three types of infestations: (1) pediculosis pubis, caused by Phthirus pubis (pubic or crab louse); (2) pediculosis corporis, caused by Pediculus humanus corporis (body louse); and (3) pediculosis capitis, caused by Pediculus humanus capitis (head louse). In pediculosis corporis, except in heavily infested individuals, the parasite is often absent from the body but inhabits seams of clothing in the axillae, beltline or collar.

Common findings in a person who is infested include pruritus (itching), nits (eggs of lice) on hair shafts, lice on skin or clothes and, occasionally with pubic lice, blue macules on the inner thighs or lower abdomen. The drugs of choice are the pediculicides permethrin and maldison (malathion) in lotions or shampoos; local public health officers or school nurses usually recommend the optimal current treatment regimen, including use of medicated shampoo and combing of hair with a fine-tooth comb to remove nits. Affected family members may also require treatment, and hairbrushes, hats, clothing, bedding etc require cleaning.

Treatment of scabies (mite infestation)

Scabies is a parasitic infestation caused by the itch mite Sarcoptes scabiei. It is an obligate parasite of humans and is transmitted by close contact with an infested individual. It bores into the horny layers of the skin in cracks and folds (almost exclusively at night), causing irritation and pruritus. The infestation in adults is usually generalised over the body, especially in web spaces between fingers, wrists, elbows and buttocks.

The acaricide of choice is permethrin cream or lotion, two applications 1 week apart. This is considered more effective than crotamiton or benzyl benzoate. Family members and close contacts should also be treated, and items such as bedding, clothes and soft toys should be sprayed.

Actions and uses

Topical corticosteroids are generally indicated for direct relief of inflammatory and pruritic dermatoses, with fewer systemic effects than from oral or parenteral administration; these drugs are discussed in greater detail in Chapters 35 and 47 (see Drug Monograph 35-1). They are used topically for their anti-inflammatory, antipruritic, vasoconstrictor and immunosuppressant actions in various types of dermatitis (eczema) and psoriasis, and in skin reactions to insect bites and sunburn. Topical corticosteroids may also stabilise epidermal lysosomes in the skin, and fluorinated steroids have antiproliferative (antimitotic) actions.

Adverse drug reactions

Adverse reactions for topical corticosteroids include skin atrophy and striae, acneiform eruptions, burning sensations, dryness, itching, hypopigmentation, purpura and haemorrhage, hirsutism (usually facial), folliculitis, alopecia (usually of scalp) and masking or aggravation of fungal infections. Contact dermatitis can be precipitated as an allergic reaction to topical corticosteroids, which may be difficult to distinguish from the inflammatory condition for which the drug is being applied.

If a significant amount of the corticosteroid is absorbed, systemic adverse effects can occur, with suppression of the hypothalamic–pituitary–adrenal axis and the classical cushingoid effects of moon face, fluid retention, skin striae, weak skin and bones, hypertension, immunosuppression, overgrowth of microorganisms leading to secondary infections, glaucoma and poor wound healing.

Potencies

Fluorinated corticosteroids are particularly recommended for topical application to thickened skin because of their potency, lipid solubility (hence topical efficacy) and low tendency to cause sodium retention. In decreasing order of potency, some topical corticosteroids are: betamethasone dipropionate^f> betamethasone valerate^f, mometasone, triamcinolone^f> clobetasone^f, flumethasone^f, methylprednisolone > desonide^f, hydrocortisone. (Those marked ^f are fluorinated compounds; potencies can vary depending on ester form and strength of formulation.)

Acute inflammatory eruptions usually respond to the medium- and low-potency steroids, whereas chronic hyperkeratotic lesions require potent or highly potent drugs.

Formulations

Corticosteroids are available in a wide range of topical formulations that are stable, easy to apply and rapid-acting, causing no pain, discolouration or odour on application. Inhalation of corticosteroids (see Drug Monograph 28-4) in treatment and prevention of asthma is a specialised topical application, in this case to the mucous membranes and thence to the smooth muscle of the airways.

Types of formulations for topical application of corticosteroids include creams, ointments, lotions, sprays, gels and scalp lotions, at various strengths. Combination preparations with antifungal or antibacterial antibiotics are also available for use in inflammatory dermatitis with a large component of infection.

The vehicle (aerosol, cream, gel, lotion, ointment, solution or tape) in which the corticosteroid is placed can alter the therapeutic efficacy. Corticosteroid penetration of the skin is enhanced by (in decreasing order of effectiveness) ointments, gels, creams and lotions. As a result of their occlusive nature, ointments hydrate the stratum corneum, enhancing steroid penetration. Lotions, sprays and gels are well suited to hairy areas or for lesions that are oozing and wet. Creams and ointments are suited to dry, scaling, thickened and pruritic areas.

The rate of transcutaneous penetration after application also influences therapeutic efficacy. It is limited by three factors: the rate of dissolution of the drug in the vehicle, the rate of passive diffusion of the drug across membranes and the drug penetration rate through the stratum corneum. Inflamed or moist skin absorbs topical steroids to a greater degree than thick or lichenified skin. Occlusive dressings (e.g. using an occlusive ointment base or wrapping in plastic cling-wrap, see Figure 48-3) increase the hydration of the skin and penetration of the drug up to 100-fold, hence systemic adverse effects are possible.

Dosage and administration

For most topical formulations, the adult dosage is one or two applications daily as directed. Application frequency depends on the site, response of the cutaneous eruption to medication and application technique.

In some conditions resistant to milder treatment, intralesional injection of corticosteroids is used. Triamcinolone is most often used, injected for example into the lesions of keloid scars, acne cysts or alopecia areata.

Calcineurin inhibitors

Pimecrolimus is a new calcineurin inhibitor related to tacrolimus and sirolimus, which are used mainly to prevent transplant rejection, and temsirolimus, an mTOR inhibitor used as an anti-angiogenesis agent in renal cell cancer therapy. These agents block T-cell activation and thus prevent release of inflammatory mediators. Pimecrolimus is indicated for short-term or intermittent use in treatment of psoriasis and eczema, applied twice daily as a cream. It can be used safely in children over 3 months, which is a benefit in childhood dermatoses. Main adverse reactions are local stinging and erythema and secondary infections.

TNF-alpha antagonists

Tumour necrosis factor-alpha (TNF-α) is an important regulator of inflammation, and antagonists of its activity are some of the newer anti-inflammatory agents proving effective in treatment of psoriasis. Etanercept is a TNF-α receptor fusion protein, while adalimumab, infliximab and golimumab are monoclonal antibodies against TNF. They are given by injection, and reactions at the infusion or injection site are common. Serious adverse effects include opportunistic infections and reactivation of infections (especially tuberculosis). There may also be increased risk of multiple sclerosis and of malignancies.

Eczema

Eczema, also known as dermatitis, is an inflammatory condition with genetic predisposition in which skin becomes red, itchy, scaly, moist and blistered. Emollient moisturisers are indicated to maintain skin hydration, tar preparations (coal tar, ichthammol) are used for their antipruritic effects and topical corticosteroids for antiinflammatory effects. The potent new immunosuppressant pimecrolimus is second-line therapy. Antibiotics may be required for infected patches of skin, and antihistamines, sedatives or analgesics for relief from itching. UVR therapy and avoidance of triggering factors such as soaps, perfumes and preservatives are also useful. Strategies with no proven benefit include homoeopathy, Chinese herbs, dietary restrictions, massage therapy, reduction of house dust and salt baths.

Atopic dermatitis is common in young children, with prevalence of 10%–20% in those under 10 years; itching and infections are likely. Prevention is best, with education of parents and avoidance of triggers and irritants such as harsh, perfumed or coloured bath additives. Topical corticosteroids are used short-term for flare-ups, and calcineurin inhibitors (e.g. pimecrolimus cream) can be administered to children over 2 years old with severe disease.

Psoriasis

Psoriasis is a common skin disease (with 2%–3% prevalence worldwide) characterised by abnormal immune response, epidermal proliferation and pink–red thickened patches of skin covered with silvery scales, with pain, itching and bleeding. Large areas of skin may be involved, with the elbows, knees, buttocks and scalp most frequently affected. There are various forms, mostly of the plaque variety; the abnormally thick lesions are packed with activated T cells causing chronic inflammation and impairing skin functions. There is a strong association with arthritis, liver disease, cardiovascular diseases and metabolic syndrome. Peak onset is in early adult years. The cause is unknown, although there appears to be an immunological involvement, and trigger factors include stress, injury, smoking, alcohol, infections and drugs such as some angiotensin-converting enzyme inhibitors, β-blockers, non-steroidal anti-inflammatory drugs (NSAIDs), quinine derivatives and lithium.

Drugs used in treatment include those administered for eczema (see above), plus the psoralens, vitamin D analogues (calcipotriol, calcitriol, which act as antiproliferative agents in the keratinocytes, see Chapter 37) and a retinoid (acitretin). In severe cases, systemic administration of the immunosuppressants cyclosporin and methotrexate (in considerably lower dose than that used in anticancer chemotherapy) may be required, with phototherapy. The new immunomodulators are also tried, especially the anti-TNF agents etanercept, infliximab and adalimumab and the new anti-interleukin antibody, ustekinumab. Adverse effects include infections, malignancies and induction of autoimmune conditions. Interestingly, some TNF inhibitors when used to treat autoimmune diseases such as rheumatoid arthritis and Crohn’s disease have actually induced psoriasis, a condition which they can be used to treat—this anomaly is being studied further. Tazarotene cream, a retinoid used in acne for its actions modifying cell proliferation and differentiation, is also indicated for use in plaque psoriasis.

Psoriasis can occur in children; it is estimated that about 27% of cases occur before the age of 16 years. Topical treatment is usually with corticosteroids or calcipotriol; more potent drugs such as methotrexate, acitretin and cyclosporin have more risks in children due to their greater potential toxicities.

Urticaria

Urticaria, or hives, is a common skin condition in which there is transient itchiness, reddening and swelling of the dermis or subcutaneous tissue; angio-oedema may be associated. In about 20% of cases, some precipitating factor may be identifiable, e.g. heat, cold, sun exposure, emotion, drugs or infection. Although a skin condition, urticaria is treated not with topical agents but with systemic antihistamines, corticosteroids, NSAIDs, tricyclic antidepressants or various other drugs. Acute severe angiooedema is a medical emergency, as airways can become obstructed, and requires treatment with parenteral adrenaline, hydrocortisone, antihistamine and fluids, together with airways support and oxygen.

Mechanism of action

The mechanism of action of retinoids is a field of active research, as retinoids are now known to be involved in a wide range of cellular functions, including in tissue repair and in regulation of growth in cancers. There are two main types of receptors for retinoids in cell nuclei: RA receptors and retinoid X receptors. Activation of RA receptors mediates steps in many biochemical pathways, including liberation of proteolytic enzymes, breakdown of cartilage, synthesis of mucopoly saccharides and steroids, morphogenesis, differentiation and proliferation of epithelial tissues, induction of neural growth factors, regulation of the immune system and development of the kidneys.

In acne, retinoids facilitate the extrusion of fatty material from existing comedones and prevent the reblocking of plugs and formation of new lesions, and have antiinflammatory actions.

Topical retinoids

Topical retinoids are used for treating mild acne vulgaris; examples of topical preparations are isotretinoin gel 0.05%, tretinoin gel and cream 0.05% (Drug Monograph 48-2), adapalene cream and gel 0.1% and tazarotene 0.05%, 0.1% cream. Gels are preferred for oily skins, and creams for those with dry skin. A useful combination product is a gel containing 0.1% adapalene and 2.5% benzoylperoxide. These medications are contraindicated in pregnancy because of the possibility of birth defects if absorbed. In severe cases of acne, retinoids may be prescribed for oral administration, with or without an oral antibiotic.

Oral retinoids

For treatment of severe cystic acne resistant to milder therapies, systemic drugs may be required. Isotretinoin 10-mg or 20-mg and acitretin 10-, 20- or 40-mg oral capsules are available. These products inhibit sebaceous gland activity and thus decrease sebum formation and secretion, and have keratolytic and anti-inflammatory effects. They are reserved to treat severe acne and have induced prolonged remissions in severe cystic acne.

Women who are pregnant or are planning to become pregnant should not use these preparations. Many spontaneous abortions have been reported, as well as major abnormalities (hydrocephalus, microcephalus and external ear and cardiovascular problems) in the fetus at birth in women who have taken retinoids during pregnancy. Because of this risk, prescription of oral retinoids is restricted to specialist dermatologists and authorised physicians. Sexually-active women of child-bearing age who are prescribed these drugs must use efficient contraceptive methods for 1 month before starting the treatment, continuously during treatment, and for 1 month (isotretinoin) or 2 years (acitretin) after cessation of treatment. The latter requirement is due to the long halflives of acitretin (>2 days) and its active metabolite etretinate (>3 months). The use of oral retinoids with topical retinoids is not recommended because additive toxicity may result.

Other adverse reactions are as described in Clinical Interest Box 48-4 for overdose and toxicity of vitamin A. In addition, there are isolated reports of acquired hearing loss after oral isotretinoin.

Keratolytics and antiseptics

In mild acne, topical keratolytics and antibacterials are the treatments of first choice. Creams and lotions containing salicylic acid, benzoyl peroxide or azelaic acid are recommended, to unblock pores by removing keratin plugs. Benzoyl peroxide slowly and continuously liberates active oxygen, producing an antibacterial, keratolytic and drying effect. The release of oxygen into the pilosebaceous and comedone area creates unfavourable growth conditions for P. acnes and reduces the release of the fatty acids from sebum. The drying vehicle also aids in shrinking the papules or pustules. There is no problem of development of resistance by the bacteria.

Azelaic acid, a straight-chain 9-carbon dicarboxylic acid, is a relatively new topical agent useful in acne. It has anti bacterial activity against P. acnes and reduces keratinisation. It has also been tried in hyperpigmentary skin disorders and in malignant melanoma. As an acid, it can cause skin irritation (burning, stinging or pruritus) if it is applied on broken skin.

Other measures include avoidance of oil- or alcoholbased cleansers or harsh soaps, and avoidance of vigorous scrubbing of the skin, as these tend to increase oiliness of the skin. Older medications include formulations with sulfur, bentonite, silica, zinc, lactic acid, urea and resorcinol as keratolytics and mild antimicrobial agents, and antiseptic washes including cetrimide, chlorhexidine, lactoferrin, alpha-hydroxy-acids or triclosan. Treatment ‘kits’ combining a keratolytic and an antiseptic cleanser can help improve compliance with therapy.

Antibiotics

The exact mechanism of action of topical and systemic antibiotics used in the treatment of acne is unknown, as acne is not mainly an infection nor is it contagious, but P. acnes appears to convert comedones to inflamed pustules or papules. Antibiotics may decrease the colonisation of P. acnes, thus decreasing the formation of sebaceous fatty acid byproducts and preventing the formation of new acne lesions. The antibiotics used include clindamycin, erythromycin and minocycline or doxycycline. Topical erythromycin and clindamycin gels are most commonly prescribed for mild to moderate acne, whereas oral antibiotics (tetracyclines) are generally reserved for individuals with severe acne, and for those who are intolerant or whose acne did not respond to topical agents. Antibiotic resistance can lead to treatment failures.

Hormones

Because acne is sometimes associated with excess androgen production, women with acne can be treated with antiandrogen agents, which reduce sebum secretion. Drugs with antiandrogenic activity include cyproterone acetate, spironolactone and flutamide (see Chapter 39) and oestrogens, usually prescribed in a combined oral contraceptive pill (Chapter 40). It is important that the preparation not contain an oestrogen with significant androgenic activity.

Extent and depth of burns

The proportion of body surface area affected is estimated by the ‘rule of nines’ for adults (see Figure 48-4A). If large areas of skin are burnt, there is great danger of infection to the patient; it is estimated that about 75% of people suffering 30% burns or more are likely to die of infection and its consequences.

Figure 48-4 Extent of body burns: percentage and thickness. A The ‘rule of nines’ in describing percentage of adult body burned: the head (front and back) and the arms each count as 9%, the front and back of the trunk each count as 18%, each leg as 18%, and the groin area as the remaining 1% of body surface area. B Diagram of layers of skin and subcutaneous tissue, showing definition of burn depth. Thus second-degree burns are those in which the superficial or deep layers of the dermis are damaged, causing blistering.

Burns are classified by degree, which is determined by the depth of skin involved within a local area (see Figure 48-4B). First-degree or superficial-thickness burns involve only the epidermis, causing erythema with characteristic dry, painful reddening and inflammation (e.g. overexposure to sun or flash burn). Second-degree or partial-thickness burns involve the epidermis extending into the dermis and may be superficial or involve deep dermal necrosis. Epithelial regeneration may extend from the deep skin appendages, such as hair follicles and sebaceous glands, which penetrate the dermis. This burn is characterised by a moist, blistered, very painful surface (e.g. flash or scald burns from non-viscous liquids). Third-degree or fullthickness burns involve destruction of the entire epidermis and dermis and adnexal structures, and are characterised by white, opaque, dry, leathery skin or coagulated, charred skin without sensation as a result of the destruction of nerve endings (e.g. flame burns or hot viscous liquids). Fourth-degree burns extend into subcutaneous fat, muscle or bone, appear black and dry and cause scarring.

Partial- or full-thickness burns must be thought of as open wounds with the accompanying danger of infection. Normal body flora organisms including Staphylococcus, Candida and Pseudomonas become pathogenic. If the tissue becomes anoxic and necrotic, anaerobic organisms such as Clostridium tetani and C. perfringens can grow. Mixed infections with multiple organisms occur frequently. The immune system can become suppressed because of injury and shock, with resulting poor defence mechanisms. Infection must be prevented or treated.

The severity of electrical burns depends on the current received, the condition of the skin (e.g. cuts, abrasions and moisture, which lower resistance) and duration of contact, which can be affected by flexor muscles contracting and inhibiting release from the power source. Electrical burns result in necrosis of more tissue than thermal burns. Chemical burns occur after contact with strong acid or alkali; the initial treatment is water irrigation of the affected area followed by neutralisation.

First-aid treatment of burns

An important first-aid treatment for minor and major burns regardless of cause (chemical, electrical or thermal) is to cool the wound immediately to remove irritants, decrease inflammation and constrict blood vessels; this reduces the permeability of the blood vessels and reduces oedema formation. Recommended first aid is to flush the burned area and hot clothing with cool running water (10–15̊C) for 20–30 minutes. The more quickly the wound is cooled, the less tissue damage there is likely to be and the less subsequent morbidity and need for surgery. No greasy ointments, butter or dressings should be applied, because these agents inhibit loss of heat from the burn, which increases both discomfort and tissue damage. After prolonged cool washing, the burn can be covered with cling wrap or sterile sheet until the person can be transported for medical attention. Major burns need referral to a burns unit (see Clinical Interest Box 48-5).

Drugs used in management of burns patients

Burned patients treated in an emergency room or burns unit are stabilised with intravenous fluids, given analgesics for pain and sedated if necessary; they may require immunisation against tetanus. Catheterisation may be necessary to measure urinary output, depending on the patient’s status. After stabilisation, the burn wound is cleaned with a mild soap and water, and a sterile, non-adherent dressing is applied to the wound.

Burned patients have a sustained increase in release of stress hormones, including corticosteroids and catecholamines, leading to a prolonged hypermetabolic state with greatly increased metabolic rate and increased requirements for energy, carbohydrates, proteins, fats, vitamins, minerals and antioxidants. Depending on the state of the patient, these may have to be supplied by parenteral nutrition. Beta-blockers have been used to help reduce the catabolic effects of burn injury and reverse protein breakdown.

Small, uncontaminated burns that can be adequately dressed do not require topical or oral antimicrobials. Silver sulfadiazine is usually preferred because of its broad-spectrum activity and because it is easy to apply to the burned site (see Drug Monograph 48-3). There is some concern about potential toxicity of silver to various host (patient) cells. New formulations with nanocrystalline silver particles are proving to have stronger antimicrobial activity with reduced frequency of dressing changes.

Povidone–iodine has been used in some centres, and it also penetrates eschar (the dead, separated, damaged skin). Povidone–iodine causes pain on application, however, and hardens the eschar area when dry. An ancient remedy that is regaining popularity is honey: in some studies of treatments for superficial or partial-thickness burns, honey covered by sterile gauze showed favourable results in terms of rate of healing compared with silver sulfadiazineimpregnated gauze (Clinical Interest Box 32-3). Other pharmacological management includes adequate pain relief, especially during dressing changes, and relief of severe itching in rehabilitating patients.

Pathophysiology

The pressure sore (bedsore or decubitus ulcer) is a break in the skin and underlying subcutaneous and muscle tissue caused by abnormal, sustained pressure or friction exerted over the bony prominences of the body by the object on which the body part rests. It results in vascular insufficiency and ischaemic necrosis, and most frequently affects debilitated, immunosuppressed, comatose, immobilised or paralysed patients. The prevalence of pressure ulcers ranges from about 9% in acute care facilities to 33% in critical care patients and those with spinal injuries, and up to 23% in nursing homes. In addition to the suffering of patients, the total cost to the health-care system of treating such wounds is enormous.

Local and systemic causes include local circulatory impairment, oedema or hypertension; trauma, pressure and shearing force on the lower body if the head of the bed is raised more than 30̊; loss of sensation of pressure or pain; debilitation, muscle atrophy and motor paralysis; reduction in the amount of adipose tissue between skin and underlying bone; dehydration, poor nutrition with inadequate intake of vitamins (especially vitamin C) and minerals (such as copper and zinc); obesity, infection and septicaemia; and heat and moisture (maceration), e.g. from incontinence.

Pressure sores are classified into four stages or grades (Figure 48-5):

Figure 48-5 The four grades of pressure sore (decubitus ulcer or bedsore). In grade IV, the underlying muscle and bone are affected, with the consequent risk of osteomyelitis.

The bacterial flora of pressure sores are both Gramnegative and Gram-positive organisms, which include Staphylococcus aureus, Streptococcus groups A and D, Escherichia coli, Clostridium tetani and Bacteroides, Proteus, Pseudomonas, Klebsiella and Citrobacter organisms. Chronic ulcers may be complicated by increased risk of extension to bone, causing osteomyelitis, and of development of squamous cell carcinomas.

Physical management

Pressure sores, like leg ulcers, are notoriously difficult to treat, and if possible should be prevented by watchful nursing care with frequent turning of bedridden patients and ambulation whenever possible. If ulcers do develop, maximum activity is even more essential to relieve pressure, optimise the muscle pump and venous return and stimulate circulation. Wound management has become a specialised area of nursing and podiatry, with many techniques and dressings available (see Heyneman et al [2008]; Dermatology Expert Group [2009]).

A treatment plan for pressure sores should take into consideration four basic principles:

A person with a full-thickness loss of skin may require surgical intervention either to debride and cover the ulcer area or to stabilise the wound. Physical therapies that have been tried include electrical stimulation, infrared and UV radiation, laser therapy and ultrasound.

Pharmacological management

Systemic antibiotics are not usually indicated, as adequate drug levels are not reached in granulating wounds, but may be needed in difficult-to-treat infected pressure sores; for sepsis, osteomyelitis, bacteraemia and advancing cellulitis; and as an adjunct to surgical management. Metronidazole is an antibacterial agent used systemically to treat grade III and IV decubitus ulcers infected with anaerobic bacteria. (A topical metronidazole gel is used to treat acne rosacea in adults.)

Medicated dressings

Sterile, non-stick dressings are applied to the ulcer or wound to keep it moist, as moist wounds heal more effectively and faster than dry wounds. Antiseptic dressings include those impregnated with chlorhexidine, povidone–

Drugs at a glance 48: Drugs treating skin disorders

iodine, silver, collagen, collagenase, honey or triclosan; there is also a dressing impregnated with the antibiotic framycetin. Finely powdered sterile gelatin is available for dusting into wounds, where it stimulates the growth of granulation tissue and healing of ulcers; the gelatin protein is gradually resorbed naturally. Packs of sterile calcium alginate fibres are used in bleeding or exuding wounds to act as haemostatics by releasing calcium, filling wounds and aiding coagulation. Unless pain or exudation occurs, dressings can be left on the wound for days or weeks, as constant removal of dressings delays healing. Bioengineered tissue substitutes such as epidermal cells or artificial fibres can help protect wounds and encourage healing.

Pharmacological treatments

Dressings similar to those used in pressure sores may be used, such as those impregnated with antiseptics (iodine, povidone–iodine, peroxides, ethacridine, levamisole, prop ylene glycol) or with adsorbents (alginates, carmellose, cadexomers, foam, hydrocolloids) or other medicaments (zinc oxide, glycerol).

Some relatively new treatments include: