Drugs and the skin

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Chapter 17 Drugs and the skin

Thomas K.K. Ha

Synopsis

This account is confined to therapy directed primarily at the skin and covers the following topics:

• Dermal pharmacokinetics.

image Vehicles for presenting drugs to the skin.

• Selected topical preparations.

image Emollients and barrier preparations
image Topical analgesics
image Antipruritics
image Analgesics
image Adrenal corticosteroids
image Sunscreens
image Drug-specific rashes.

• Approaches to some skin disorders.

image Psoriasis
image Acne
image Urticaria
image Atopic dermatitis.

Dermal pharmacokinetics

Human skin is a highly efficient self-repairing barrier that permits terrestrial life by regulating heat and water loss while preventing the ingress of noxious chemicals and microorganisms. A drug applied to the skin may diffuse from the stratum corneum into the epidermis and then into the dermis, to enter the capillary microcirculation and thus the systemic circulation (Fig. 17.1). The features of components of the skin in relation to drug therapy, whether for local or systemic effect, are worthy of examination.

image

Fig. 17.1 Principal pathways operating during topical drug delivery.

The principal barrier to penetration resides in the multiple-layered lipid-rich stratum corneum. The passage of a drug through this layer is influenced by its:

• Physicochemical features: lipophilic drugs can utilise the intracellular route because they readily cross cell walls, whereas hydrophilic drugs principally take the intercellular route, diffusing in fluid-filled spaces between cells.

• Molecular size: most therapeutic agents suitable for topical delivery measure 100–500 Da.

Drugs are presented in vehicles (bases1), designed to vary in the extent to which they increase hydration of the stratum corneum; e.g. oil-in-water creams promote hydration (see below). Increasing the water content of the stratum corneum via occlusion or hydration generally increases the penetration of both lipophilic and hydrophilic materials. This may be due to an increased fluid content of the lipid bilayers. The stratum corneum and stratum granulosum layers become more similar with hydration and occlusion, thus lowering the partition coefficient of the molecule passing through the interface. Some vehicles also contain substances intended to enhance penetration by reducing the barrier properties of the stratum corneum, e.g. fatty acids, terpenes, surfactants. Encapsulation of drugs into vesicular liposomes may enhance drug delivery to specific compartments of the skin, e.g. hair follicles.

Absorption through normal skin varies with site. From the sole of the foot and the palm of the hand it is relatively low; it increases progressively on the forearm, trunk, head and neck; and on the scrotum and vulva absorption is very high. Where the skin is damaged by inflammation, burn or exfoliation, barrier function is reduced and absorption is further increased.

If an occlusive dressing (impermeable plastic membrane) is used, absorption increases by as much as 10-fold (plastic pants for babies are occlusive, and some ointments are partially occlusive). Systemic toxicity can result from use of occlusive dressing over large areas.

Transdermal delivery systems are now used to administer drugs via the skin for systemic effect; the advantages and disadvantages of this route are discussed on page 88.

Vehicles for presenting drugs to the skin

Dermatological formulations tend to be classified by their physical properties. The formulations below are described in order of decreasing water content. All water-based formulations must contain preservatives, e.g. chlorocresol, but these rarely cause allergic contact dermatitis.

Liquid formulations

Water or a solvent is the most important component. The preparation can be a soak, a bath or a paint. Wet dressings are generally used to cleanse, cool and relieve pruritus in acutely inflamed lesions, especially where there is much exudation, e.g. atopic eczema. The frequent reapplication and the cooling effect of evaporation of the water reduce the inflammatory response by inducing superficial vasoconstriction (an effect enhanced when alcohol is present in the formulation). Sodium chloride solution 0.9%, stringent substances, e.g. aluminium acetate lotion, or potassium permanganate soaks or compresses of approximately 0.01–0.05% can be used. The use of lotions (wet dressings) over very large areas can reduce body temperature dangerously in the old or the very ill.

Two-phase or multiple liquid shake lotions, e.g. calamine lotion, are essentially a convenient way of applying a powder to the skin with additional cooling due to evaporation of the water. They are contraindicated when there is much exudate, because crusts form. Lotions, after evaporation, sometimes produce excessive drying of the skin, but this can be reduced if oils are included, as in oily calamine lotion.

Creams

These are emulsions of either oil in water (washable; cosmetic ‘vanishing’ creams) or water in oil. The water content allows the cream to rub in well. A cooling effect (cold creams) is obtained with both groups as the water evaporates.

Oil-in-water creams,

e.g. aqueous cream (see emulsifying ointment, below), mix with serous discharges and are especially useful as vehicles for water-soluble drugs. They may contain a wetting (surface tension-reducing) agent (cetomacrogol). Various other ingredients, e.g. calamine, zinc, may be added to it.

Water-in-oil creams,

e.g. oily cream, zinc cream, behave like oils in that they do not mix with serous discharges, but their chief advantage over ointments (below) is that the water content makes them easier to spread and they give a better cosmetic effect. They act as lubricants and emollients, and can be used on hairy parts. Water-in-oil creams can be used as vehicles for lipid-soluble substances.

Creams, being less occlusive and effective at hydrating the stratum corneum, are not as effective for drug delivery as ointments.

Ointments

Ointments are greasy and thicker than creams. Some are both lipophilic and hydrophilic, i.e. by occlusion they promote dermal hydration, but are also water miscible. Other ointment bases are composed largely of lipid; by preventing water loss they have a hydrating effect on skin and are used in chronic dry conditions. Ointments contain fewer preservatives and are less likely to sensitise. There are two main kinds:

Water-soluble ointments

include mixtures of macrogols and polyethylene glycols; their consistency can be varied readily. They are easily washed off and are used in burn dressings, as lubricants and as vehicles that readily allow passage of drugs into the skin, e.g. hydrocortisone.

Emulsifying ointment is made from emulsifying wax (cetostearyl alcohol and sodium lauryl sulphate) and paraffins. Aqueous cream is an oil-in-water emulsion of emulsifying ointment.

Non-emulsifying ointments

do not mix with water. They adhere to the skin to prevent evaporation and heat loss, i.e. they can be considered a form of occlusive dressing (with increased systemic absorption of active ingredients); skin maceration may occur. Non-emulsifying ointments are helpful in chronic dry and scaly conditions, such as atopic eczema, and as vehicles; they are not appropriate where there is significant exudation. They are difficult to remove except with oil or detergents, and are messy and inconvenient, especially on hairy skin. Paraffin ointment contains beeswax, paraffins and cetostearyl alcohol.

Collodions and gels

Collodions are preparations of a thickening agent, e.g. cellulose nitrate (pyroxylin) dissolved in an organic solvent. The solvent evaporates rapidly and the resultant flexible film is used to hold a medicament, e.g. salicylic acid, in contact with the skin. They are irritant and inflammable, and are used to treat only small areas of skin.

Gels or jellies are semi-solid colloidal solutions or suspensions used as lubricants and as vehicles for drugs. They are sometimes useful for treating the scalp.

Pastes

Pastes, e.g. zinc compound paste, are stiff, semi-occlusive ointments containing insoluble powders. They are very adhesive and are valuable for treating highly circumscribed lesions while preventing spread of active ingredients on to surrounding skin. Their powder content enables them to absorb a moderate amount of discharge. They can be used as vehicles, e.g. coal tar paste, which is zinc compound paste with 7.5% coal tar. Lassar’s paste is used as a vehicle for dithranol in the treatment of well-circumscibed plaque psoriasis.

Solid preparations

Solid preparations such as dusting powders, e.g. zinc starch and talc,2 may cool by increasing the effective surface area of the skin and they reduce friction between skin surfaces by their lubricating action. Although usefully absorbent, they cause crusting if applied to exudative lesions. They may be used alone or as specialised vehicles for, e.g., fungicides.

Emollients and barrier preparations

Emollients

hydrate the skin, and soothe and smooth dry scaly conditions. They need to be applied frequently as their effects are short lived. There is a variety of preparations but aqueous cream, in addition to its use as a vehicle (above), is effective when used as a soap substitute. Various other ingredients may be added to emollients, e.g. menthol, camphor or phenol for its mild antipruritic effect, and zinc and titanium dioxide as astringents.3

Barrier preparations

Many different kinds have been devised for use in medicine, in industry and in the home to reduce dermatitis. They rely on water-repellent substances, e.g. silicones (dimethicone cream), and on soaps, as well as on substances that form an impermeable deposit (titanium, zinc, calamine). The barrier preparations are useful in protecting skin from discharges and secretions (colostomies, nappy rash), but are ineffective when used under industrial working conditions. Indeed, the irritant properties of some barrier creams can enhance the percutaneous penetration of noxious substances. A simple after-work emollient is more effective.

Silicone sprays and occlusives, e.g. hydrocolloid dressings, may be effective in preventing and treating pressure sores. Masking creams (camouflaging preparations) for obscuring unpleasant blemishes from view are greatly valued by patients.4 They may consist of titanium oxide in an ointment base with colouring appropriate to the site and the patient.

Topical analgesics

Counterirritants and rubefacients

are irritants that stimulate nerve endings in intact skin to relieve pain in skin (e.g. post-herpetic), viscera or muscle supplied by the same nerve root. All produce inflammation of the skin, which becomes flushed – hence the term ‘rubefacients’. The best counterirritants are physical agents, especially heat. Many compounds have been used for this purpose and suitable preparations contain salicylates, nicotinates, menthol, camphor and capsaicin. Specific transient receptor potential (TRP) cation channels involved in sensory perception in skin can be stimulated by these drugs. The moderate heat receptor TRPV1 is sensitive to capsaicin as well as moderate heat (42–52°C), whereas TRPM8 is stimulated specifically by temperatures below 26°C and by menthol.

Topical non-steroidal anti-inflammatory drugs (NSAIDs)

can be used to relieve musculoskeletal pain.

Local anaesthetics

Lidocaine and prilocaine are available as gels, ointments and sprays to provide reversible block of conduction along cutaneous nerves. Benzocaine and amethocaine (tetracaine) carry a high risk of sensitisation.

Volatile aerosol sprays, beloved by sports people, produce analgesia by cooling and by placebo effect.

Antipruritics

Mechanisms of itch are both peripheral and central. Itch (at least histamine-induced itch) is not a minor or low-intensity form of pain. Cutaneous histamine injection stimulates a specific group of C fibres with very low conduction speeds and large fields, distinct from those that signal pain. Second-order neurones then ascend via the spinothalamic tract to the thalamus. In the central nervous system, endogenous opioid peptides are released (the opioid antagonist naloxone can relieve some cases of intractable itch). Itch signalling appears to be under tonic inhibition by pain. If pain after histamine injection is reduced by opioid then itch results and, if pain is ablated by lidocaine, itch sensation increases. Prolonged inflammation in the skin may lead to peripheral and central sensitisation, thus leading non-itchy stimuli to be reinterpreted as itch.

Liberation of histamine and other autacoids in the skin also contributes and may be responsible for much of the itch of urticarial allergic reactions. Histamine release by bile salts may explain some, but not all, of the itch of obstructive jaundice. It is likely that other chemical mediators, e.g. serotonin, progesterone metabolites, endogenous opioids and prostaglandins, are involved.

Generalised pruritus

In the absence of a primary dermatosis it is important to search for an underlying cause, e.g. iron deficiency, liver or renal failure, and lymphoma, but there remain patients in whom the cause either cannot be removed or is not known. Antihistamines (H1-receptor), especially chlorphenamine and hydroxyzine orally, are used for their sedative or anxiolytic effect (except in urticaria); they should not be applied topically over a prolonged period because of risk of allergy. In severe pruritus, a sedative antidepressant may also help.

The itching of obstructive jaundice might be relieved by the anion exchange resin colestyramine, an endoscopically placed nasobiliary drain, or phototherapy with ultraviolet B light. Naltrexone offers short-term relief of the pruritus associated with haemodialysis.

Localised pruritus

Scratching or rubbing seems to give relief by converting the intolerable persistent itch into a more bearable pain. A vicious cycle can be set up in which itching provokes scratching, and scratching leads to infected skin lesions that itch, as in prurigo nodularis. Covering the lesion or enclosing it in a medicated bandage so as to prevent any further scratching or rubbing may help. Multiple intralesional triamcinolone injections and thalidomide may be used in recalcitrant cases of prurigo nodularis.

Topical corticosteroid preparations are used to treat the underlying inflammatory cause of pruritus, e.g. in eczema. A cooling application such as 0.5–2% menthol in aqueous cream is temporarily antipruritic.

Calamine and astringents (aluminium acetate, tannic acid) may help. Local anaesthetics do not offer any long-term solution and, as they are liable to sensitise the skin, they are best avoided. Topical doxepin can be helpful in localised pruritus but extensive use induces sedation and may cause allergic contact dermatitis.

Pruritus ani

is managed by attention to any underlying disease, e.g. haemorrhoids, parasites, and hygiene. Emollients, e.g. washing with aqueous cream and a weak corticosteroid with antiseptic/anticandida application, may be used briefly to settle any acute eczema or superinfection. Some cases are a form of neurodermatitis, and an antihistamine with anti-anxiolytic properties, e.g. hydroxyzine, or a low-dose sedative antidepressant, e.g. doxepin, and mirtazapine, may be helpful. Secondary contact sensitivity, e.g. to local anaesthetics, must be considered.

Adrenocortical steroids

Actions

Adrenal steroids possess a range of actions, of which the following are relevant to topical use:

• Inflammation is suppressed, particularly when there is an allergic factor, and immune responses are reduced.

• Antimitotic activity suppresses proliferation of keratinocytes, fibroblasts and lymphocytes (useful in psoriasis, but also causes skin thinning).

• Vasoconstriction reduces ingress of inflammatory cells and humoral factors to the inflamed area; this action (blanching effect on human skin) has been used to measure the potency of individual topical corticosteroids (see below).

Penetration into the skin is governed by the factors outlined at the beginning of the chapter. The vehicle should be appropriate to the condition being treated: an ointment for dry, scaly conditions; a water-based cream for weeping eczema.

Uses

Adrenal corticosteroids should be considered a symptomatic and sometimes curative, but not preventive, treatment. Ideally a potent steroid (see below) should be given only as a short course and reduced as soon as the response allows. Corticosteroids are most useful for eczematous disorders (atopic, discoid, contact), whereas dilute corticosteroids are especially useful for flexural psoriasis (where other therapies are highly irritant). Adrenal corticosteroids of highest potency are reserved for recalcitrant dermatoses, e.g. lichen simplex, lichen planus, nodular prurigo and discoid lupus erythematosus.

Topical corticosteroids should be applied sparingly. The ‘fingertip unit’5 is a useful guide in educating patients (Table 17.1). The difficulties and dangers of systemic adrenal steroid therapy are sufficient to restrict such use to serious conditions (such as pemphigus and generalised exfoliative dermatitis) not responsive to other forms of therapy.

Table 17.1 Fingertip unit dosimetry for topical corticosteroids (distance from the tip of the adult index finger to the first crease)

image

Guidelines for the use of topical corticosteroids

• Use for symptom relief and not prophylactically.

• Choose the appropriate therapeutic potency (Table 17.2), e.g. mild for the face. In cases likely to be resistant, use a very potent preparation, e.g. for 3 weeks, to gain control, after which change to a less potent preparation.

• Choose the appropriate vehicle, e.g. a water-based cream for weeping eczema, an ointment for dry, scaly conditions.

• Prescribe in small but adequate amounts so that serious overuse is unlikely to occur without the doctor knowing, e.g. weekly quantity by group (see Table 17.2): very potent 15 g; potent 30 g; other 50 g.

• Occlusive dressing should be used only briefly. Note that babies’ plastic pants are an occlusive dressing as well as being a social amenity.

• If it’s wet, dry it; if it’s dry, wet it. The traditional advice contains enough truth to be worth repeating.

• One or two applications a day are all that is usually necessary.

Table 17.2 Topical corticosteroid formulations conventionally ranked according to therapeutic potency

Potency Formulations
Very potent Clobetasol (0.05%); also formulations of diflucortolone (0.3%), halcinonide
Potent Beclometasone (0.025%); also formulations of betamethasone, budesonide, desoximetasone, diflucortolone (0.1%), fluclorolone, fluocinolone (0.025%), fluocinonide, fluticasone, hydrocortisone butyrate, mometasone (once daily), triamcinolone
Moderately potent Clobetasone (0.05%); also formulations of alclometasone, clobetasone, desoximetasone, fluocinolone (0.00625%), fluocortolone, fluandrenolone
Mildly potent Hydrocortisone (0.1–1.0%); also formulations of alclomethasone, fluocinolone (0.0025%), methylprednisolone

Important note: the ranking is based on agent and its concentration; the same drug appears in more than one rank.

Choice

Topical corticosteroids are classified according to both drug and potency, i.e. therapeutic efficacy in relation to weight (see Table 17.2). Their potency is determined by the amount of vasoconstriction a topical corticosteroid produces (McKenzie skin-blanching test6) and the degree to which it inhibits inflammation. Choice of preparation relates both to the disease and the site of intended use. High-potency preparations are commonly needed for lichen planus and discoid lupus erythematosus; weaker preparations (hydrocortisone 0.5–2.5%) are usually adequate for eczema, for use on the face and in childhood.

When a skin disorder requiring a corticosteroid is already infected, a preparation containing an antimicrobial is added, e.g. fusidic acid or clotrimazole. When the infection has been eliminated, the corticosteroid may be continued alone. Intralesional injections are used occasionally to provide high local concentrations without systemic effects in chronic dermatoses, e.g. hypertrophic lichen planus and discoid lupus erythematosus.

Adverse effects

Used with restraint, topical corticosteroids are effective and safe. Adverse effects are more likely with formulations ranked therapeutically as very potent or potent in Table 17.2.

Short-term use

Infection may spread.

Long-term use

Skin atrophy can occur within 4 weeks and may or may not be fully reversible. It reflects loss of connective tissue, which also causes striae (irreversible) and generally occurs at sites where dermal penetration is high (face, groins, axillae).

Other effects include:

local hirsutism; perioral dermatitis (especially in young women), which responds to steroid withdrawal and may be mitigated by tetracycline by mouth for 4–6 weeks; depigmentation (local); monomorphous acne (local). Potent corticosteroids should not be used on the face unless this is unavoidable. Systemic absorption can lead to all the adverse effects of systemic corticosteroid use. Fluticasone propionate and mometasone furoate are rapidly metabolised following cutaneous absorption, which may reduce the risk of systemic toxicity. Suppression of the hypothalamic–pituitary axis occurs readily with overuse of the very potent agents, and when 20% of the body is under an occlusive dressing with mildly potent agents.

Other complications of occlusive dressings include infections (bacterial, candidal) and even heat stroke when large areas are occluded. Antifungal cream containing hydrocortisone and used for vaginal candidiasis may contaminate the urine and misleadingly suggest Cushing’s syndrome.7

Applications to the eyelids may get into the eye and cause glaucoma.

Rebound exacerbation of the disease can occur after abrupt cessation of therapy. This can lead the patient to reapply the steroid and so create a vicious cycle.

Allergy. Corticosteroids, particularly hydrocortisone and budesonide, or other ingredients in the formulation, may cause allergic contact dermatitis. The possibility of this should be considered when expected benefit fails to occur, e.g. varicose eczema.

Sunscreens (sunburn and photosensitivity)

Ultraviolet (UV) solar radiation

(Fig. 17.2) is defined as:

• UVA (320–400 nm), which damages collagen, contributes to skin cancer and drug photosensitivity.

• UVB (280–320 nm), which is 1000 times more active than UVA, acutely causes sunburn and chronically skin cancer and skin ageing.

• UVC (200–280 nm), which is prevented, at present, from reaching the earth at sea level by the stratospheric ozone layer, although it can cause skin injury at high altitude.

image

Fig. 17.2 The ultraviolet component of the electromagnetic spectrum.

Protection of the skin

Protection from UV radiation is effected by:

Absorbent sunscreens

These organic chemicals absorb UVB and UVA at the surface of the skin (generally more effective for UVB).

UVB protection is provided by aminobenzoic acid and aminobenzoates (padimate-O), cinnamates, salicylates, camphors.

UVA protection is provided by benzophenones (mexenone, oxybenzone), dibenzoylmethanes.

Reflectant sunscreens

Opaque inorganic minerals such as titanium dioxide, zinc oxide and calamine act as a physical barrier to UVB and UVA (especially zinc oxide); they are cosmetically unattractive, but the newer micronised preparations are more acceptable. Because they are able to protect against visible light, they are especially useful in photosensitivity disorders, e.g. porphyria.

The performance of a sunscreen is expressed as the sun protective factor (SPF), which refers to UVB (UVA is more troublesome to measure and the protection is indicated by a star rating system, with four stars providing the greatest). A SPF of 10 means that the dose of UVB required to cause erythema must be 10 times greater on protected than on unprotected skin. The SPF should be interpreted only as a rough guide; consumer use is more haphazard, and less liberal amounts are applied to the skin in practice. The benefits of using active agents including vitamins, antioxidants, osmolytes and DNA repair enzymes in sunscreens and cosmetics to counteract the inherent photochemical processes that can induce DNA damage in skin cells is unproven.

Sunscreens should protect against both UVB and UVA. Absorbent and reflectant components are combined in some preparations. The washability of the preparation (including removal by sweat and swimming) is also relevant to efficacy and frequency of application; some penetrate the stratum corneum (padimate-O) and are more persistent than others.

Uses

Sunscreens are no substitute for light-impermeable clothing and sun avoidance (especially during peak hours of UV light). Daily application of sunscreen appears to protect more against UV-induced skin changes than intermittent use of the product. Methodical use has been demonstrated to reduce the incidence of cutaneous squamous cell carcinoma. Sunscreens are especially beneficial in protecting those who are photosensitive due to drugs (below) or disease, i.e. for photodermatoses such as photosensitivity dermatitis, polymorphic light eruption, cutaneous porphyrias and lupus erythematosus.

Treatment of mild sunburn is usually with a lotion such as oily calamine lotion. Severe cases are helped by topical corticosteroids. NSAIDs, e.g. indometacin, can help if given early, by preventing the formation of prostaglandins.

Drug photosensitivity

Drug photosensitivity means that an adverse effect occurs as a result of drug plus light, usually UVA; sometimes even the amount of UV radiation from fluorescent light tubes is sufficient.

Systemically taken drugs that can induce photo-sensitivity are many, the most common being the following:8

• Antimitotics: dacarbazine, vinblastine, taxanes, methotrexate.

• Antimicrobials: demeclocycline, doxycycline, nalidixic acid, sulfonamides.

• Antipsychotics: chlorpromazine, prochlorperazine.

• Cardiac arrhythmic: amiodarone.

• Diuretics: furosemide, chlorothiazide, hydrochlorothiazide.

• Fibric acid derivatives, e.g. fenofibrate.

• Hypoglycaemics: tolbutamide.

• NSAIDs: piroxicam.

• Psoralens (see below).

• Antifungals: voriconazole (extreme photoxicity and heightened risk of SCC and melanoma).

Topically applied substances that can produce photosensitivity include:

• Para-aminobenzoic acid and its esters (used as sunscreens).

• Coal tar derivatives.

• Psoralens from juices of various plants, e.g. bergamot oil.

• 6-Methylcoumarin (used in perfumes, shaving lotions, sunscreens).

There are two forms of photosensitivity:

Phototoxicity,

like drug toxicity, is a normal effect of too high a dose of UV light in a subject who has been exposed to the drug. The reaction is like severe sunburn. The threshold returns to normal when the drug is withdrawn. Some drugs, notably NSAIDs, induce a ‘pseudoporphyria’, clinically resembling porphyria cutanea tarda and presenting with skin fragility, blisters and milia on sun-exposed areas, notably the backs of the hands.

Photoallergy,

like drug allergy, is a cell-mediated immunological effect that occurs only in some people, and which may be severe with a small dose. Photoallergy due to drugs is the result of a photochemical reaction caused by UVA in which the drug combines with tissue protein to form an antigen. Reactions may persist for years after the drug is withdrawn; they are usually eczematous.

Systemic protection,

as opposed to application of drug to exposed areas, should be considered when the topical measures fail.

Antimalarials such as hydroxychloroquine may be effective for short periods in polymorphic light eruption and in cutaneous lupus erythematosus.

Psoralens (obtained from citrus fruits and other plants), e.g. methoxsalen, are used to induce photochemical reactions in the skin. After topical or systemic administration of the psoralen and subsequent exposure to UVA there is an erythematous reaction that goes deeper than ordinary sunburn and may reach its maximum only after 48 h (sunburn maximum is 12–24 h). Melanocytes are activated and pigmentation occurs over the following week. This action is used to repigment areas of disfiguring depigmentation, e.g. vitiligo in black-skinned persons.

In the presence of UVA the psoralen interacts with DNA, forms thymine dimers and inhibits DNA synthesis. Psoralen plus UVA (PUVA) treatment is used chiefly in severe psoriasis (a disease characterised by increased epidermal proliferation) and cutaneous T-cell lymphoma.

Severe adverse reactions can occur with psoralens and UV radiation, including sunburn, increased risk of skin cancer (due to mutagenicity inherent in their action), cancer of the male genitalia, cataracts and accelerated skin ageing; the treatment is used only by specialists.

Chronic exposure to sunlight induces wrinkling and yellowing due to the changes in the dermal connective tissue. Topical retinoids are used widely in an attempt to reverse some of these tissue changes. Public pursuit of novel tanning strategies, including the unregulated subcutaneous self-administration of synthetic analogues of alpha-melanocyte-stimulating hormone (alpha-MSH), has been reported. Medical practitioners should be aware that these agents can complicate the clinical presentation of patients with changing moles and suspected melanoma.

Miscellaneous compounds

Keratolytics

are used to destroy unwanted tissue, including warts and corns. Great care is obviously necessary to avoid ulceration. They include trichloroacetic acid, salicylic acid and many others. Resorcinol and sulphur are mild keratolytics used in acne. Salicylic acid may enhance the efficacy of a topical steroid in hyperkeratotic disorders.

Tars

are mildly antiseptic, antipruritic and inhibit keratinisation in an ill-understood way. They are safe in low concentrations and are used in psoriasis. Photosensitivity occurs and tar–UVB regimens are highly effective therapies for extensive psoriasis. There are very many preparations, which usually contain other substances, e.g. coal tar and salicylic acid ointment.

Ichthammol

is a sulphurous, tarry, distillation product of fossilised fish (obtained in the Austrian Tyrol); it has a weaker effect than coal tar.

Zinc oxide

provides mild astringent, barrier and occlusive actions. Calamine is basic zinc carbonate that owes its pink colour to added ferric oxide. It has a mild astringent action, and is used as a dusting powder and in shake and oily lotions.

Urea

is used topically to assist skin hydration, e.g. in ichthyosis.

Insect repellents,

e.g. against mosquitoes, ticks, fleas, such as DEET (diethyl toluamide), dimethyl phthalate. These are applied to the skin and repel insects principally by vaporisation. They must be applied to all exposed skin, and sometimes also to clothes, if their objective is to be achieved (some damage plastic fabrics and spectacle frames). Their duration of effect is limited by the rate at which they vaporise (dependent on skin and ambient temperature), by washing off (sweat, rain, immersion) and by mechanical factors causing rubbing (physical activity). They can cause allergic and toxic effects, especially with prolonged use.

Benzyl benzoate

may be used on clothes; it resists one or two washings.

Cutaneous drug reactions

Drugs applied locally or taken systemically often cause rashes. These take many different forms and the same drug may produce different rashes in different people. Types of drug rash include:

• Exanthems.

• Acute generalised exanthematous pustulosis.

• Fixed drug rash.

• Stevens–Johnson syndrome/erythema multiforme/toxic epidermal necrolysis.

• Hypersensitivity reaction including DRESS (drug rash with eosinophilia and systemic symptoms), e.g. hepatitis. The pathogenesis of DRESS is likely to be multifactorial. The factors include deficient detoxification of a drug metabolite in patients who are genetically susceptible, drug interactions, and direct effects of drug-specific T cells. Recent reports of co-infection with human herpesvirus (HHV)-6 or HHV-7 and a transient hypogammaglobulinaemia may prove important in anticonvulsant hypersensitivity.

Some of the mechanisms involved in drug-induced cutaneous reactions are described in Box 17.1.

Box 17.1 Mechanisms of cutaneous drug reactions

Immunological mechanisms

• IgE dependent

• Cytotoxic

• Immune complex mediated

• Cell mediated

Non-immunological mechanisms

• Overdosage

• Cumulative toxicity

• Delayed toxicity

• Drug?drug?food interactions

• Excacerbation of disease

Idiosyncratic

• Drug rash with eosinophilia and systemic symptoms (DRESS)

• Toxic epidermal necrolysis/Stevens?Johnson syndrome

• Drug reactions in setting of HIV

• Drug-induced lupus

Although drugs may change, the clinical problems remain depressingly the same: a patient develops a rash; he or she is taking many different tablets; which, if any, of these caused the eruption, and what should be done about it? It is no answer simply to stop all drugs, although the fact that this can often be done casts some doubt on the patient’s need for them in the first place. All too often, potentially valuable drugs are excluded from further use on totally inadequate grounds. Clearly some guidelines are useful, but no simple set of rules exists that can cover this complex subject:9

1. Can other skin diseases be excluded and are the skin changes compatible with a drug cause? Clinical features that indicate a drug cause include the type of primary lesion (blisters, pustules), distribution of lesions (acral lesions in erythema multiforme), mucosal involvement and evidence of systemic involvement (fever, lymphadenopathy, visceral involvement).

2. Which drug is most likely to be responsible? Document all of the drugs the patient has been exposed to and the date of introduction of each drug. Determine the interval between commencement date and the date of the skin eruption. Chronology is important, with most reactions occurring about 10–12 days after starting a new drug or within 2–3 days in previously exposed patients. A search of standard literature sources of adverse reactions, including the pharmaceutical company data, can be helpful in identifying suspect drugs.

3. Are any further tests worthwhile? Excluding infectious causes of skin eruptions is important, e.g. viral exanthems, mycoplasma. A skin biopsy in cases of non-specific dermatitis is helpful, as a predominance of eosinophils would support a drug precipitant.

4. Is any treatment needed? Supporting the ill patient and stopping the causative drug is crucial.

Drug-specific rashes

Despite great variability, some hints at drug-specific or characteristic rashes from drugs taken systemically can be discerned; some examples are as follows:

• Acne and pustular: corticosteroids, androgens, ciclosporin, penicillins.

• Allergic vasculitis: sulfonamides, NSAIDs, thiazides, chlorpropamide, phenytoin, penicillin, retinoids.

• Anaphylaxis: X-ray contrast media, penicillins, angiotensin-converting enzyme (ACE) inhibitors.

• Bullous pemphigoid: furosemide (and other sulfonamide-related drugs), ACE inhibitors, penicillamine, penicillin, PUVA therapy.

• Eczema: penicillins, phenothiazines.

• Exanthematic/maculopapular reactions are the most frequent; unlike a viral exanthem, the eruption typically starts on the trunk; the face is relatively spared. Causes include antimicrobials, especially ampicillin, sulfonamides and derivatives (sulfonylureas, furosemide and thiazide diuretics).

• Morbilliform (measles-like) eruptions typically recur on rechallenge.

• Erythema multiforme: NSAIDs, sulfonamides, barbiturates, phenytoin, paclitaxel.

• Erythema nodosum: dermatitis and sulfonamides, oral contraceptives, prazosin.

• Exfoliative erythroderma: gold, phenytoin, carbamazepine, allopurinol, penicillins, neuroleptics, isoniazid.

• Fixed eruptions are eruptions that recur at the same site, often circumoral, with each administration of the drug: phenolphthalein (laxative self-medication), sulfonamides, quinine (in tonic water), tetracycline, barbiturates, naproxen, nifedipine.

• Hair loss: cytotoxic anticancer drugs, acitretin, oral contraceptives, heparin, androgenic steroids (women), sodium valproate, gold.

• Hypertrichosis: corticosteroids, ciclosporin, doxasosin, minoxidil.

• Lichenoid eruption: β-adrenoceptor blockers, chloroquine, thiazides, furosemide, captopril, gold, phenothiazines.

• Lupus erythematosus: hydralazine, isoniazid, procainamide, phenytoin, oral contraceptives, sulfazaline.

• Purpura: thiazides, sulfonamides, sulfonylureas, phenylbutazone, quinine. Aspirin induces a capillaritis (pigmented purpuric dermatitis).

• Photosensitivity: see above.

• Pemphigus: penicillamine, captopril, piroxicam, penicillin, rifampicin.

• Pruritus unassociated with rash: oral contraceptives, phenothiazines, rifampicin (cholestatic reaction).

• Pigmentation: oral contraceptives (chloasma in photosensitive distribution), phenothiazines, heavy metals, amiodarone, chloroquine (pigmentation of nails and palate, depigmentation of the hair), minocycline.

• Psoriasis may be aggravated by β-blockers, lithium and antimalarials.

• Scleroderma-like: bleomycin, sodium valproate, tryptophan contaminants (eosinophila–myalgia syndrome).

• Serum sickness: immunoglobulins and other immunomodulatory blood products.

• Stevens–Johnson syndrome and toxic epidermal necrolysis (TENS): e.g. anticonvulsants, sulfonamides, aminopenicillins, NSAIDs, allopurinol, chlormezanone, corticosteroids.

• Urticaria and angioedema: penicillins, ACE inhibitors, gold, NSAIDs, e.g. aspirin, codeine.

Patients with the acquired immunodeficiency syndrome (AIDS) have an increased risk of adverse reactions, which are often severe. Recovery after withdrawal of the causative drug generally begins within a few days, but lichenoid reactions may not improve for weeks.

Diagnosis

The patient’s drug history may give clues. Reactions are commoner during early therapy (days) than after the drug has been given for months. Diagnosis by purposeful readministration of the drug (challenge) is not recommended, especially in patients suffering a generalised effect or with mucosal involvement, as it may precipitate toxic epidermal necrolysis.

Patch and photopatch tests are useful in contact dermatitis as they reproduce the causative process, but should be performed only by those with special experience. Fixed drug eruptions can sometimes be reproduced by patch testing with the drug over the previously affected site.

Intradermal tests introduce all the problems of allergy to drugs, e.g. metabolism, combination with protein, fatal anaphylaxis.

Treatment

Treatment involves supportive care and removal of the causative drug. Use cooling applications and antipruritics; use a histamine H1-receptor blocker systemically for acute urticaria. The use of adrenal corticosteroids is controversial. It may be useful for severe exanthems if the incriminated drug is crucial for other concurrent disease, and is useful for internal organ disease involvement in DRESS. The use of human-derived immunoglobulin infusions is increasingly advocated in the treatment of toxic epidermal necrolysis.

Safety monitoring

Several drugs commonly used in dermatology should be monitored regularly for (principally systemic) adverse effects. These include:

• Aciclovir (plasma creatinine).

• Azathioprine (blood count and liver function).

• Colchicine (blood count, plasma creatinine).

• Ciclosporin (plasma creatinine).

• Dapsone (liver function, blood count including reticulocytes).

• Methotrexate (blood count, liver function).

• PUVA (liver function, antinuclear antibodies).

• Aromatic retinoids (liver function, plasma lipids).

The patient and doctor must always remain vigilant about drug–drug and drug–food interactions that may result in toxicity, e.g. methotrexate/trimethoprim, ciclosporin/grapefruit juice.

Individual disorders

Table 17.3 is not intended to give the complete treatment of even the commoner skin conditions but merely to indicate a reasonable approach. Secondary infections of ordinarily uninfected lesions may require added topical or systemic antimicrobials. Analgesics, sedatives or tranquilisers may be needed in painful or uncomfortable conditions, or where the disease is intensified by emotion or anxiety.

Table 17.3 Summary of treatment for selected skin disorders

Condition Treatment Remarks
Androgenic alopecia Topical 2% or 5% minoxidil is worth trying. Finasteride can stop hair loss and increase hair density in 50% of men The response occurs in 4–12 months; hair loss resumes when therapy is stopped
Alopecia areata Potent topical or intralesional corticosteroids may be useful in the short term Although distressing, the condition is often self-limiting. A few individuals have responded to PUVA or contact sensitisation induced by diphencyprone
Dermatitis herpetiformis Dapsone is typically effective in 24 h, or sulfapyridine. Long-term gluten-free diet Methaemoglobinaemia may complicate dapsone therapy
Hirsutism in women Combined oestrogen–progestogen contraceptive pill: cyproterone plus ethinylestradiol (Dianette). Spironolactone, cimetidine have been used Local cosmetic approaches: epilation by wax or electrolysis; depilation (chemical), e.g. thioglycollic acid, barium sulfide. The result of laser epilation is transient and may paradoxically induce excess hair growth in certain individuals
Hyperhidrosis Astringents reduce sweat production, especially aluminium chloride hexahydrate. Antimuscarinics, e.g. glycopyrrolate (topical or systemic), may help and may be used with iontophoresis. Botulinum toxin can be used to provide temporary remission (3–4 months) and is most useful for the axilla. Sympathectomy is used occasionally but may be complicated by compensatory hyperhidrosis The characteristic smell is produced by bacterial action, so cosmetic deodorants contain antibacterials rather than substances that reduce sweat
Impetigo Topical antibiotics, e.g. mupirocin, fusidic acid In severe cases (resistant organisms) systemic macrolide, cephalosporin antibiotics
Intertrigo Cleansing lotions, powders to cleanse, lubricate and reduce friction. A dilute corticosteroid with anticandidal cream is often helpful No evidence that new azoles are superior to nystatin
Larva migrans Cryotherapy. Albendazole (single dose) or topical thiabendazole  
Lichen planus Antipruritics (menthol); potent topical corticosteroid PUVA or retinoids in severe cases
Lichen simplex (neurodermatitis) Antipruritics (menthol); topical corticosteroid; sedating antihistamines Occluding the lesion so as to prevent scratch–itch cycle to patient. Focused cognitive behaviour therapy may be helpful
Lupus erythematosus Photoprotection (including against UVA) is essential. Potent adrenal corticosteroid topically or intralesionally. Hydroxychloroquine or mepacrine. Monitor for retinal toxicity when treatment is long term. Other agents include acetretin and auranofin  
Malignancies Actinic keratoses and Bowen’s disease can be treated with topical 5-fluorouracil (skin irritation is to be expected) or cryotherapy. Imiquimod is a possible topical alternative. Extensive lesions may respond to photodynamic therapy: the skin is sensitised using a topical haematoporphyrin derivative, e.g. aminolaevulinic acid, and irradiated with a visible light or laser source. Cutaneous T-cell lymphoma in its early stages is best treated conservatively; PUVA will often clear lesions for several months or years; alternatives include topical nitrogen mustard, e.g. carmustine, radiotherapy and the retinoid bexarotene  
Nappy rash Prevention: rid re-usable nappies of soaps, detergents and ammonia by rinsing. Change frequently and use an emollient cream, e.g. aqueous cream, to protect skin. Costly disposable nappies are useful but must also be changed regularly. Cure: zinc cream or calamine lotion plus above measures  
Onychomycosis Confirm dermatophyte infection with microscopy and culture. Terbinafine, two pulses of itraconazole or 6–9 months of once-weekly fluconazole is used for fingernail onychomycosis. For toenail disease, terbinafine is used for 12–16 weeks; 3–4 pulses of itraconazole or fluconazole once per week for 9–15 months can be used The newer oral antifungals have not been approved for use in children. Surgical removal of infected nail maybe required and reinfection is common
Pediculosis (lice) Permethrin, phenothrin, carbaryl or malathion (anticholinesterases, with safety depending on more rapid metabolism in humans than in insects, and on low absorption) Usually two applications 7 days apart to kill lice from eggs that survive the first dose. Physical measures including regular combing and keeping hair short are important
Pemphigus and pemphigoid Milder cases can be treated with topical corticosteroids and tetracyclines. Systemic steroids and immunosuppressants (azathioprine, mycophenylate) are useful for severe disease. Plasmapheresis, IVIg and rituximab may also be useful for resistant cases  
Pityriasis rosea Antipruritics and emollients as appropriate; UVB phototherapy The disease is self-limiting
Pyoderma gangrenosum Topical therapies may include corticosteroids, tacrolimus. Systemic corticosteroids are usually effective. Immunosuppressives, e.g. ciclosporin, may be used for steroid-sparing effect. Some patients respond to dapsone, minocycline or clofazamine  
Rosacea Topical metronidazole and systemic tetracycline. Retinoids are useful for severe cases Control pustulation in order to prevent secondary scarring and rhinophyma
Scabies (Sarcoptes scabiei) Permethrin dermal cream. Alternatives include benzyl benzoate or ivermectin (single dose), especially for outbreaks in closed communities. Crotamiton or calamine for residual itch. Topical corticosteroid to settle persistent hypersensitivity Apply to all members of the household, immediate family or partner. Change underclothes and bedclothes after application
Seborrhoeic dermatitis: dandruff (Pityriasis capitis) A proprietary shampoo with pyrithione, selenium sulfide or coal tar; ketoconazole shampoo in more severe cases. Occasionally a corticosteroid lotion may be necessary  
Tinea capitis In children griseofulvin for 6–8 weeks is effective and safe. Terbinafine for 4 weeks is effective against Trichophyton spp. Microsporum will respond to 6 weeks’ therapy with terbinafine Antifungal shampoos can reduce active shedding in patients treated with oral antifungals
Tinea pedis Most cases will respond to tolnaftate or undecenoic acid creams. Allylamine (terbinafine) creams are possibly more effective than azoles in resistant cases  
Venous leg ulcers Limb compression is the mainstay of therapy. Other agents including pentoxifylline and skin grafts are useful adjuncts to compression therapy  
Viral warts All treatments are destructive and should be applied with precision. Salicylic acid in collodion daily. Many other caustic (keratolytic) preparations exist, e.g. salicylic and lactic acid paint or gel. For plantar warts, formaldehyde or glutaraldehyde; for plantar or anogenital warts, podophyllin (antimitotic). Follow the manufacturer’s instructions meticulously. If one topical therapy fails it is worth trying a different type. Topical imiquimod is an alternative for genital warts; it is irritant. Careful cryotherapy (liquid nitrogen) Warts often disappear spontaneously. Cryotherapy can cause ulceration, damage the nail matrix and leave permanent scars

Psoriasis

In psoriasis there is increased epidermal undifferentiated cell proliferation and inflammation of the epidermis and dermis. The consequence of increased numbers of immature horn cells containing abnormal keratin is that an abnormal stratum corneum is formed. Drugs are used to:

• dissolve keratin (keratolysis)

• inhibit cell division.

An emollient such as aqueous cream will reduce the inflammation. The proliferated cells may be eliminated by a dithranol (antimitotic) preparation applied accurately to the lesions (but not on the face or scalp) for 1 h and then removed as it is irritant to normal skin and stains skin, blond hair and fabrics. A suitable regimen may begin with 0.1% dithranol, increasing to 1%. Dithranol is available in cream bases or in Lassar’s paste (the preparations are not interchangeable). It is used daily until the lesions have disappeared and may produce prolonged remissions of psoriasis. Tar (antimitotic) preparations are used in a similar way, are less irritating to normal skin and are commonly used for psoriasis of the scalp.10

Topical adrenal corticosteroids

act principally by reducing inflammation. Application, especially under occlusive dressings, can be very effective at suppressing the disease, but increased doses (concentrations) become necessary and rebound, which may be severe, follows withdrawal. For this reason potent corticosteroids should never be used except for lesions on the scalp, palms and soles. Corticosteroids of mild potency may be used for flexural psoriasis where other drugs are too irritating.

Systemic corticosteroid administration should be avoided, for high doses are needed to suppress the disease, which is liable to recur in a more unstable form when treatment is withdrawn, as it must be if complications of long-term steroid therapy are to be avoided.

Calcipotriol and tacalcitol

are analogues of calcitriol, the most active natural form of vitamin D (see p. 551). They inhibit cell proliferation and encourage cell differentiation. Although they have less effect on calcium metabolism than does calcitriol, excessive use (more than 100 g/week) can raise the plasma calcium concentration.

Vitamin A

(retinols) plays a role in epithelial function, and the retinoic acid derivative acitretin (orally) inhibits psoriatic hyperkeratosis over 4–6 weeks. Acitretin should be used in courses (6–9 months) with intervals (3–4 months). It is teratogenic, like the other vitamin A derivatives. It is not recommended for use in women of childbearing potential because the drug is stored in the liver and in fat, and active metabolites are released many months after cessation of therapy.

UVB light

is effective in guttate psoriasis and potentiates the effects of topical agents such as calcipotriol (act by reducing cell division), antimitotic agents like tar (Goeckerman’s regimen) and dithranol (Ingram’s regimen). Oral psoralen followed by UVA light (PUVA) may be used to clear severe cases of psoriasis, with remissions of more than a year being achievable. Long-term PUVA therapy is associated with an increased risk of cutaneous squamous cell carcinoma and melanoma development (especially in those given maintenance treatment).

Ciclosporin,

the systemic calcineurin inhibitor (see p. 523), has been instrumental in shifting the focus of psoriasis research from keratinocyte abnormalities to immune perturbations. It has a rapid onset of action and is useful in achieving remissions in all forms of psoriasis. Monitoring of blood pressure and renal function is mandatory. Severe adverse effects, including renal toxicity, preclude its being used as long-term suppressive therapy.

Since the introduction of ciclosporin for psoriasis, much research has focused on new ways of disrupting T lymphocytes and the cytokines involved in the induction and maintenance of psoriasis. These drugs target specific cellular events, e.g. induction of T-lymphocytic apoptosis, inhibition of tumour necrosis factor. The exact role of these promising therapies is still evolving.

Folic acid antagonists,

e.g. methotrexate, can also suppress epidermal activity and inhibit T and B lymphocytes, and are especially useful when psoriasis is severe and remits rapidly with other treatments. Methotrexate is particularly of use if there is associated disabling arthritis. Platelet count, renal and liver function must be monitored regularly. When 1.5 g of the total dose has been taken, liver biopsy should be considered, especially in those with predisposing hepatic steatosis.

The last decade has witnessed a significant advance in the management of refractory moderate-to-severe psoriasis with the introduction of biological therapies to clinical practice. These drugs target specific cellular events, e.g. induction of T-lymphocytic apoptosis, inhibition of tumour necrosis factor. Three classes of biological therapies have been used: T-cell inhibitors, tumour necrosis factor (TNF)-α inhibitors, and interleukin (IL-12 and IL-23) inhibitors. The first of these to be introduced, the T-cell inhibitor efalizumab, was withdrawn because of a rare association with progressive multifocal leukoencephalopathy (PML). In contrast, anti-TNF treatments are now firmly established, offering a high level of efficacy and a good safety record. Ustekinumab, by targeting the p40 subunit common to interleukins 12 and 23, offers a viable alternative to anti-TNFs in the treatment of moderate-to-severe psoriasis. The identification of PML as a serious, but statistically rare risk of efalizumab demonstrates the strengths and weaknesses of the current drug approval and pharmacovigilance processes for fully measuring the safety of a drug. Patients and clinicians need to be aware of the relative completeness and limitations of existing safety data of a drug when selecting a treatment.

It is plain from this brief outline that treatment of psoriasis requires considerable judgement and choice will depend on the patient’s sex, age and the severity of the condition. Topical therapies such as calcipotriol, tar or dithranol-containing compounds should be the mainstay of limited mild psoriasis. Topical corticosteroids can be used for psoriasis inversus under close supervision, as overuse can lead to cutaneous atrophy. Phototherapy is useful for widespread psoriasis where compliance with topical treatments is difficult. Resistant disease is best managed by the specialist who may utilise a rotation of treatments, including retinoids, methotrexate, ciclosporin, UVB plus dithranol and PUVA + acitretin, to reduce the unwanted effects of any single therapy. Fumaric acid compounds, hydroxyurea and specific biological agents are useful for severe cases.

Acne

Acne vulgaris results from disordered function of the pilosebaceous follicle whereby abnormal keratin and sebum (the production of which is androgen driven) form debris that plugs the mouth of the follicle. Propionibacterium acnes colonises the debris. Bacterial action releases inflammatory fatty acids from the sebum, resulting in inflammation. Acne is a chronic disorder and if uncontrolled can lead to irreversible scarring.

The following measures are used progressively and selectively as the disease becomes more severe; they may need to be applied for up to 3–6 months:

• Mild keratolytic (exfoliating, peeling) formulations unblock pilosebaceous ducts, e.g. benzoyl peroxide, sulphur, salicylic acid, azelaic acid.

• Systemic or topical antimicrobial therapy (tetracycline, erythromycin, lymecycline) is used over months (expect 30% improvement after 3 months). Bacterial resistance is not a problem; benefit is due to suppression of bacterial lipolysis of sebum, which generates inflammatory fatty acids. (Avoid minocycline because of adverse effects, including raised intracranial pressure and drug-induced lupus.)

• Vitamin A (retinoic acid) derivatives reduce sebum production and keratinisation. Vitamin A is a teratogen. Tretinoin (Retin-A) is applied topically (but not in combination with other keratolytics). Tretinoin should be avoided in sunny weather and in pregnancy. Benefit is seen in about 10 weeks. Adapalene, a synthetic retinoid, may be better tolerated as it is less irritant. Isotretinoin (Roaccutane) orally is highly effective (a single course of treatment to a cumulative dose of 100 mg/kg is curative in 94% of patients), but is known to be a serious teratogen; its use should generally be confined to the more severe cystic and conglobate cases, where other measures have failed. Fasting blood lipids should be measured before and during therapy (levels of cholesterol and triglycerides may rise). Women of childbearing potential should be fully informed of this risk, pregnancy-tested before commencement and use contraception for 4 weeks before, during and for 4 weeks after cessation.11 Other adverse effects are described, including mood change and severe depression.

• Hormone therapy. The objective is to reduce androgen production or effect by using (1) oestrogen, to suppress hypothalamic–pituitary gonadotrophin production, or (2) an antiandrogen (cyproterone). An oestrogen alone as initial therapy to get the acne under control or, in women, the cyclical use of an oral contraceptive containing 50 micrograms of oestrogen diminishes sebum secretion by 40%. A combination of ethinylestradiol and cyproterone (Dianette) orally is also effective in women (it has a contraceptive effect, which is desirable as the cyproterone may feminise a male fetus).

Urticaria

Acute urticaria (named after its similarity to the sting of a nettle, Urtica) and angioedema usually respond well to H1-receptor antihistamines, although severe cases are relieved more quickly with use of adrenaline/epinephrine (adrenaline injection 1 mg/mL:0.1–0.3 mL s.c.). A systemic corticosteroid may be needed in severe cases, e.g. urticarial vasculitis.

In some individuals, urticarial weals are provoked by physical stimuli, e.g. friction (dermographism), heat or cold. Exercise may induce weals, particularly on the upper trunk (cholinergic urticaria). Physical urticarias are particularly challenging to treat.

Chronic urticaria usually responds to an H1-receptor antihistamine with low sedating properties, e.g. cetirizine or loratidine. Terfenadine is also effective, but may cause dangerous cardiac arrhythmias if the recommended dose is exceeded or if it is administered with drugs (or grapefruit juice) that inhibit its metabolism. But lack of sleep increases the intensity of itch (similar to pain), and a sedating antihistamine may be useful at night. H2-receptor antihistamines may be added for particularly resistant cases. In some patients with antibodies against the Fc receptor on mast cells, immunosuppressive therapies (e.g. ciclosporin, methotrexate or intravenous immunoglobulin) may be required.

Hereditary angioedema, with deficiency of C1-esterase inhibitor (a complement inhibitor), may not respond to antihistamines or corticosteroid but only to fresh frozen plasma or, preferably, C1-inhibitor concentrate. Delay in initiating the treatment may lead to death from laryngeal oedema (try adrenaline/epinephrine i.m. in severe cases). Icatibant is a selective and specific antagonist of bradykinin B2 receptors. It has been approved in Europe for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults (with C1-esterase-inhibitor deficiency). For long-term prophylaxis an androgen (stanozolol, danazol) can be effective. Hereditary angioedema does not manifest as simple urticaria.

Atopic dermatitis

Atopic dermatitis is a chronic condition, and treatment must be individualised and centred around preventive measures. Successful management includes the elimination of precipitating and exacerbating factors, and maintaining the skin barrier function by use of topical or systemic agents.

Immunological triggers of atopic dermatitis vary and can include aeroallergens, detergents (including soaps), irritants, climate and microorganisms. Identification and modification of these factors is useful.

Antiseptic-containing soap substitutes are useful in reducing pro-inflammatory Staphylococcus aureus colonies.

In acute weeping dermatitis, lotions, wet dressing or soaks (sodium chloride, potassium permanganate) are used.

In subacute and chronic disease, skin care with occlusive emollients helps to offset the xerosis (dryness) that creates microfissures in the skin and disturbs its normal barrier function. Topical corticosteroids form the cornerstone of pharmacological therapy. In general, the lowest-potency topical steroid should be used initially and higher-potency agents considered only if these fail, the aim being to switch to intermittent steroid use protocols once the disease has been controlled. Higher potency agents are usually inappropriate for young children and highly permeable areas. Very potent steroids should not be used for longer than 2 consecutive weeks to minimise the likelihood of unwanted effects.

The calcineurin inhibitors, tacrolimus and pimecrolimus, are effective topically. Local irritation may result but they do not cause skin atrophy and so are especially useful on the face. Long-term safety data are still lacking and the FDA cautions against long-term use in children on the grounds of cutaneous carcinogenesis.

Sedating H1-receptor antihistamines with anxiolytic properties may assist with sleep and nocturnal itch. A 2-week course of systemic corticosteroid is useful, especially in cases of acute allergic contact dermatitis. Long-term oral immunosuppression with ciclosporin, mycophenylate or azathioprine should be undertaken only in specialist centres. Although there is minimal objective improvement in atopic dermatitis with UVB phototherapy, patients have consistently reported subjective improvement in itch.

Skin infections

Superficial bacterial infections,

e.g. impetigo, eczema, are commonly staphylococcal or streptococcal. They are treated with a topical antimicrobial for less than 2 weeks, applied twice daily after removal of crusts that prevent access of the drug, e.g. with a povidone–iodine preparation. Very extensive cases need systemic treatment.

Topical sodium fusidate and mupirocin are preferred (as they are not used ordinarily for systemic infections and therefore development of drug-resistant strains is less likely to have any serious consequences). Framycetin and polymyxins are also used. Absorption of neomycin from all topical preparations can cause serious injury to the eighth cranial nerve. It is also a contact sensitiser.

When prolonged treatment is required, topical antiseptics (e.g. chlorhexidine) are preferred and bacterial resistance is less of a problem.

Combination of an antimicrobial drug with a corticosteroid (to suppress inflammation) can be useful for secondarily infected eczema.

The disadvantages of antimicrobials are contact allergy and developments of resistant organisms (which may cause systemic, as well as local, infection). Failure to respond may be due to the development of a contact allergy (which may be masked by corticosteroid).

Infected leg ulcers generally do not benefit from long-term antimicrobials, although topical metronidazole is useful when the ulcer is malodorous due to colonisation with Gram-negative organisms. An antiseptic (plus a protective dressing with compression) is preferred if antimicrobial therapy is needed.

Nasal carriers of staphylococci may be cured (often temporarily) by topical mupirocin or neomycin plus chlorhexidine.

Deep bacterial infections,

e.g. boils, generally do not require antimicrobial therapy, but if they do it should be systemic. Cellulitis requires systemic chemotherapy initially with benzylpenicillin and flucloxacillin.

Infected burns are treated with a variety of antimicrobials, including silver sulfadiazine and mupirocin.

Fungal infections

Superficial dermatophyte or Candida infections purely involving the skin can be treated with a topical imidazole, e.g. clotrimazole, miconazole. Pityriasis versicolor, a yeast infection, primarily involves the trunk in young adults. It responds to topical antifungals or selenium sulfide preparations; severe infection may require systemic itraconazole. It tends to recur and regular treatments are frequently necessary. Invasion of hair or nails by a dermatophyte or a deep mycosis requires systemic therapy; terbinafine is the most effective drug. Terbinafine and griseofulvin are ineffective against yeasts, for which itraconazole is an alternative. Itraconazole can be used in weekly pulses each month for 3–4 months; it is less effective against dermatophytes than terbinafine.

Viral infections

Topical antivirals, e.g. aciclovir, penetrate the stratum corneum poorly. Aciclovir is used systemically for severe infections, e.g. eczema herpeticum.

Parasitic infection

Topical parasiticides (see Table 17.3 for details).

Disinfection and cleansing of the skin

Numerous substances are used according to circumstances:

• For skin preparation prior to injection: ethanol or isopropyl alcohol.

• For disinfection: chlorhexidine salts, cationic surfactant (cetrimide), soft soap, povidone–iodine (iodine complexed with polyvinylpyrrolidone), phenol derivatives (hexachlorophene, triclosan) and hydrogen peroxide.

Guide to further reading

Bystryn J.C., Rudolph J. Pemphigus. Lancet. 2005;366:61–73.

Currie B.J., McCarthy J.S. Permethrin and ivermectin for scabies. N. Engl. J. Med.. 2010;362(8):717–725.

Hwang S.T., Janik J.E., Jaffe E.S., Wilson W.H. Mycosis fungoides and Sézary syndrome. Lancet. 2008;371(9616):945–957.

James W.D. Acne. N. Engl. J. Med.. 2005;352(14):1463–1472.

Kaplan K.P. Chronic urticaria and angioedema. N. Engl. J. Med.. 2002;346(3):175–179.

Kullavanijaya P., Lim H.W. Photoprotection. J. Am. Acad. Dermatol.. 2005;52(6):937–958.

Madan V., Lear J.T., Szeimies R.M. Non-melanoma skin cancer. Lancet. 2010;375(9715):673–685.

Naldi L., Rebora A. Clinical practice. Seborrheic dermatitis. N. Engl. J. Med.. 2009;360(4):387–396.

Nestle F.O., Kaplan D.H., Barker J. Psoriasis. N. Engl. J. Med.. 2009;361(5):496–509.

Powell F.C. Rosacea. N. Engl. J. Med.. 2005;352(8):793–803.

Rosenfield R.L. Hirsutism. N. Engl. J. Med.. 2005;353(24):2578–2588.

Schwartz R.A. Superficial fungal infections. Lancet. 2004;364:1173–1182.

Smith C.H., Barker J.N.W.N. Psoriasis and its management. Br. Med. J.. 2006;333:380–384.

Stern R.S. Treatment of photoaging. N. Engl. J. Med.. 2004;350:1526–1534.

Thompson J.F., Scolyer R., Kefford R. Cutaneous melanoma. Lancet. 2005;365:687–701.

Williams H.C. Atopic dermatitis. N. Engl. J. Med.. 2005;352(22):2314–2324.

Yosipovitch G., Greaves M., Schmelz M. Itch. Lancet. 2003;361:690–694.

1 The chief ingredient of a mixture.

2 Talc is magnesium silicate. It must not be used for dusting surgical gloves as it causes granulomas if it gets into mounds or body cavities.

3 Astringents are weak protein precipitants, e.g. tannins, salts of aluminium and zinc.

4 In the UK, the Red Cross offers a free cosmetic camouflage service through hospital dermatology departments.

5 The distance from the tip of the index finger to the first skin crease.

6 McKenzie A W, Stoughton R B 1962 Method for comparing percutaneous absorption of steroids. Archives of Dermatology 86:608–610.

7 Kelly C J G, Ogilvie A, Evans J R et al 2001 Raised cortisol excretion rate in urine and contamination by topical steroids. British Medical Journal 322:594.

8 Data from The Medical Letter 1995;37:35.

9 Hardie R A, Savin J A 1979 Drug-induced skin diseases. British Medical Journal 1:935 (to whom we are grateful for the quotation and classification).

10 But are not without risk. A 46-year-old man whose psoriasis was treated with topical corticosteroids, UV light and tar was seen in the hospital courtyard bursting into flames. A small ring of fire began several centimetres above the sternal notch and encircled his neck. The patient promptly put out the fire. He admitted to lighting a cigarette just before the fire, the path of which corresponded to the distribution of the tar on his body (Fader D J, Metzman M S 1994 Smoking, tar, and psoriasis: a dangerous combination. New England Journal of Medicine 330:1541).

11 The risk of birth defect in a child of a woman who has taken isotretinoin when pregnant is estimated at 25%. Thousands of abortions have been performed in such women in the USA. It is probable that hundreds of damaged children have been born. There can be no doubt that there has been irresponsible prescribing of this drug, e.g. in less severe cases. The fact that a drug with such a grave effect is still permitted to be available is attributed to its high efficacy. In Europe, women of childbearing age must comply with a pregnancy prevention programme and be monitored monthly while on a course of isotretinoin. In the USA, patients and their doctors and pharmacists are required by the US Food and Drug Administration (FDA) to register with the mandatory iPLEDGE distribution programme in order to receive this medication.

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