Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 18) ppt

16 Drugs and the skin SYNOPSIS This account is confined to therapy directed primarily at the skin. • Pharmacokinetics of the skin • Topical preparations:Vehicles for presenting drugs to the skin; Emollients, barrier preparations and dusting powders;Topical analgesics; Antipruritics; Adrenocortical steroids; Sunscreens • Cutaneous adverse drug reactions • Individual disorders: Psoriasis.Acne, Urticaria, Skin infections It is easy to do more harm than good with potent drugs, and this is particularly true in skin diseases. Many skin lesions are caused by systemic or topical use of drugs, often taking the form of immediate or delayed hypersensitivity. Pharmacokinetics The stratum corneum (superficial keratin layer) is both the principal barrier to penetration of drugs into the skin and a reservoir for drugs; a corticosteroid may be detectable even 4 weeks after a single application. Drugs are presented in vehicles, e.g. cream, ointment, and their entry into the skin is determined by the: • rate of diffusion of drug from the vehicle to the surface of the skin (this depends on the type of vehicle, see below) • partitioning of the drug between the vehicle and the stratum corneum (a physicochemical feature of the individual drug) and • degree of hydration of the stratum corneum (hydration reduces resistance to diffusion of drug). Vehicles (bases 1 ) are designed to vary in the extent to which they increase the hydration of the stratum corneum; e.g. oil-in-water creams promote hydration (see below). Some vehicles also contain substances intended to enhance penetration, e.g. squalane (p. 306). 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, the scalp, the face until on the scrotum and vulva absorption is very high. Where the skin is damaged by inflammation, burn or exfoliation, 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). Serious systemic toxicity can result from use of occlusive dressing over large areas. A drug readily diffuses from the stratum corneum into the epidermis and then into the dermls, where 1 The chief ingredient of a mixture. 299 16 DRUGS AND THE SKIN it enters the capillary microcirculation of the skin, and thus the systemic circulation. There may be a degree of presystemic (first-pass) metabolism in the epidermis and dermis, a desirable feature to the extent that it limits systemic effects. Transdermal delivery systems are now used to administer drugs via the skin for systemic effect (see p. 109). Topical preparations It is convenient to think of these under the following headings: • Vehicles for presenting drugs to the skin • Emollients, barrier preparations and dusting powders • Topical analgesics • Antipruritics • Adrenocortical steroids • Sunscreens • Miscellaneous substances. VEHICLES FOR PRESENTING DRUGS TO THE SKIN The formulations 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. Lotions or wet dressings Water is the most important component. 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. Sodium chloride solution 0.9%, or solutions of astringent 2 substances, e.g. aluminium acetate lotion, or potassium permanganate soaks or compresses of approx. 0.05%, can be used. The use of lotions or 2 Astringents are weak protein precipitants, e.g. tannins, salts of aluminium and zinc. wet dressings over very large areas can reduce body temperature dangerously in the old or the very ill. Shake lotions, e.g. calamine lotion, are essentially a convenient way of applying a powder to the skin (see Dusting powders, p. 301) 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 either of 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 emul- sifying ointment, below), mix with serous discharges and are especially useful as vehicles for water-soluble active drugs. They may contain a wetting (surface tension reducing) agent (cetomacrogol). Aqueous cream is also used as an emollient (see below). 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. A dry skin is mainly short of water, and oily substances are needed to provide a barrier that reduces evaporation of water, i.e. the presence of oils contributes to epidermal hydration. Ointments Ointments are greasy and are 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 300 16 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 mac- rogols 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. Nonemulsifying 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. Nonemulsifying 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 Collodions are preparations of 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. Pastes Pastes, e.g. zinc compound paste, are stiff, semi- occlusive ointments containing insoluble powders. They are very adhesive and give good protection to circumscribed lesions, preventing spread of active ingredients to surrounding skin. Their powder content enables them to absorb a moderate amount TOPICAL PREPARATIONS 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 plaque psoriasis. EMOLLIENTS, BARRIER PREPARATIONS AND DUSTING POWDERS 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. 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, cal- amine). The barrier preparations are useful in protecting skin from discharges and secretions (colostomies, napkin rash) but they 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 the victims 3 . They may consist of titanium oxide in an ointment base with colouring appropriate to the site and the patient. Dusting powders, e.g. zinc starch and talc, 4 may 3 In the UK, the Red Cross offers a free cosmetic camouflage service through hospital dermatology departments. 4 Talc is magnesium silicate. It must not be used for dusting surgical gloves as it causes granulomas if it gets into wounds or body cavities. 301 DRUGS AND THE SKIN cool by increasing the effective surface area of the skin and they reduce friction between skin surfaces by their lubricating action. Though usefully absor- bent, they cause crusting if applied to exudative lesions. They may be used alone or as a vehicle for, e.g. fungicides. Gels or jellies are semisolid colloidal solutions or suspensions used as lubricants and as vehicles for drugs. They are sometimes useful for treating the scalp. TOPICAL ANALGESICS Counterirritants and rubefacients are irritants that stimulate nerve endings in intact skin to relieve pain in skin (e.g. postherpetic), viscera or muscle supplied by the same nerve root. All produce inflammation of the skin which becomes flushed, hence rubefacients. They are often effective though their precise mode of action is unknown. The best Counterirritants are physical agents, especially heat. Many drugs, however, have been used for this purpose and suitable preparations containing salicylates, nicotinates, menthol, camphor and capsaicin (depletes skin substance P) are also available. Topical NSAIDs (see p. 290) are 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 (see p. 422). Benzocaine and amethocaine (tetracaine) carry a high risk of sensitisation. Volatile aerosol sprays, beloved by sportspeople, produce analgesia by cooling and by placebo effect. ANTIPRURITICS Mechanisms of itch are both peripheral and central. Impulses pass along the same nerve fibres as those of pain, but the sensation experienced differs qualitatively as well as quantitatively from pain. In the CNS endogenous opioid peptides are released and naloxone can relieve some cases of intractable itch. Local 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 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 (H a receptor), especially chlor- phenamine and hydroxyzine orally, are used for their sedative or anxiolytic effect (except in urticaria); they should not be applied topically over a prolonged period for risk of allergy. In severe pruritus, a sedative antidepressant may also help. The itching of obstructive jaundice may be relieved by androgens but they may increase the jaundice. If obstruction is only partial, colestyramine and phototherapy can be useful. 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. Firm pressure with a finger may relieve the itch. A vicious cycle can be set up in which itching provokes scratching and scratching leads to skin lesions which itch, as in lichenified eczema. Covering the lesion or enclosing it in a medicated bandage so as to prevent any further scratching or rubbing may help. 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 antipruritic, probably by weak local anaesthetic action. Calamine and astringents (aluminium acetate, tannic acid) may help. Local anaesthetics do not offer any long-term solution and since they are liable to sensitise the skin they are best avoided; lignocaine is least troublesome in this respect. Topical doxepin 302 16 TOPICAL PREPARATIONS can be helpful in localised pruritus, but extensive use induces sedation; like other topical antihistamines it induces allergic contact dermatitis. Crotamiton, an acaricide, is reputed to have a specific but unexplained antipruritic action, although it is irritant. Pruritus ani is managed by attention to hygiene, emollients, e.g. washing with aqueous cream, and a weak corticosteroid with antiseptic/anticandida application used as briefly as practicable (some cases are a form of neurodermatitis). Secondary contact sensitivity, e.g. to local anaesthetics, is common. ADRENOCORTICAL STEROIDS Actions. Adrenal steroids possess a range of actions (see p. 664) 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 this 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 steroids 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. Cortico- steroids are most useful for eczematous disorders (atopic, discoid, contact) and other inflammatory conditions save those due to infection. Dilute corticosteroids are useful in psoriasis (see p. 309). Adrenal steroids of highest potency are reserved for recalcitrant dermatoses, e.g. lichen simplex, lichen planus, nodular prurigo and discoid lupus ery- thematosus. Topical corticosteroids are of no use for urticarial conditions and are contraindicated in infection, e.g. fungal, herpes, impetigo, scabies, because the infection will exacerbate and spread. Where ap- propriate, an adrenal steroid formulation may include an antimicrobial, e.g. miconazole, fusidic acid, in infected eczema. Topical corticosteroids should be applied sparingly ('Marmite rather than marmalade'). The 'finger tip unit' 5 is a useful guide in educating patients (see Table 16.1). 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. • Use for symptom relief and never prophylactically • Choose the appropriate therapeutic potency (see Table 16.2), i.e. 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, i.e. a water-based cream for weeping eczema, an ointment for dry scaly conditions. • Use a combined adrenal steroid/antimicrobial formulation if infection is present. • Advise the patient to apply the formulation very thinly, just enough to make the skin surface shine slightly. • Prescribe in small but adequate amounts so that serious overuse is unlikely to occur without the doctor knowing, e.g. weekly quantity by group (Table 16.2): very potent 15 g; potent 30 g; others 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. Choice. Corticosteroids are classified according to their therapeutic potency (efficacy), i.e. according to both drug and % concentration (see Table 16.2). 5 The distance from the tip of the adult index finger to the first crease. 303 16 16 DRUGS AND THE SKIN TABLE 16.1 Finger tip unit dosimetry for topical corticosteroids Age 3-6 months 1 -2 years 3-5 years 6-10 years Adult Face/ Neck 1 1.5 1.5 2 2.5 Arm/ Hand 1 1.5 2 2.5 Arm — 3 Hand— 1 Leg/ Foot 1.5 2 3 4.5 Foot — 2 Leg—6 Trunk (front) 1 2 3 3.5 7 Trunk (back, including buttocks) 1.5 3 3.5 5 7 TABLE 16.2 Topical corticosteroid formulations conventionally ranked according to therapeutic potency Very potent Clobetasol (0.05%) [also formulations of diflucortolone (0.3%), halcinonide] Potent Beclomethasone (0.025%) [also formulations of betamethasone, budesonide, desonide, desoxymethasone, 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, desoxymethasone, fluocinolone (0.00625%), fluocortolone, fluandrenolone, hydrocortisone plus urea (see p. 307)] 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 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, 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 clo- trimazole. When the infection is eliminated the corticosteroid may be continued alone. Intralesional injections are occasionally used 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 cortico- steroids are effective and safe. Adverse effects are more likely with formulations ranked therapeutically as very potent or potent in Table 16.2. • 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) responds to steroid withdrawal and may be mitigated by tetracycline by mouth for 4-6 weeks; depigmentation (local); 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 furcate are rapidly metabolised following cutaneous absorption which may reduce the risk of systemic toxicity. Suppression of the hypothalamic/pituitary axis readily occurs 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. 6 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 for- 6 Kelly C J et al 2001 Raised cortisol excretion rate in urine and contamination by topical steroids. British Medical Journal 322: 594. 304 16 TOPICAL PREPARATIONS mulation, may cause allergic contact dermatitis and the possibility of this should be considered where expected benefit fails to occur. SUNSCREENS (Sunburn and Photosensitivity) Ultraviolet (UV) solar radiation consists of: • UVA (320-400 nanometres): causes skin aging (damage to collagen) and probably skin cancer • UVB (290-320 nm): is 1000 times more active than UVA, acutely causes sunburn and tanning, and chronically skin cancer and skin aging • UVC (200-290 nm) is prevented, at present, from reaching the earth at sea level by the stratospheric ozone layer, though it can cause skin injury at high altitude. 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: aminobenzoic acid and aminobenzoates (padimate-O), cinnamates, salicylates, camphors. UVA protection: benzophenones (mexenone, oxybenzone), dibenzoylmethanes. Reflectant sunscreens. Inert minerals such as titanium dioxide, zinc oxide and calamine act as a physical barrier to UVB and UVA: they are cos- metically unattractive but the newer micronised preparations are more acceptable. 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 4 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. 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. Sun screens are no substitute for light- impermeable clothing and sun avoidance. They are, however, beneficial in protecting those who are photosensitive due to drugs (below) or to disease, i.e. for photodermatoses such as photosensitivity dermatitis, polymorphic light eruption, cutaneous porphyrias and lupus erythematosus. Methodical use of sunscreens appears to reduce the incidence of squamous cell carcinoma in vulnerable individuals. The lower lip receives a substantial dose of UV but may be neglected when a sunscreen is applied (specific lip-blocks are available). Sunscreens can cause allergic dermatitis or photodermatitis (but not titanium dioxide, though its vehicle may). 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. Photosensitivity Drug photosensitivity means that an adverse effect occurs as a result of drug plus light, usually UVA; sometimes even the amount of ultraviolet radiation from fluorescent light tubes is sufficient. Systemically taken drugs that can induce photo- sensitivity are many. Of the drug groups given below, those most commonly reported are: 7 antimitotics: dacarbazine, vinblastine antimicrobials: demeclocycline, doxycycline, nalidixic acid, sulphonamides antipsychotics: chlorpromazine, prochlorperazine cardiac arrhythmic: amiodarone diuretics: frusemide (furosemide), chlorothiazide, hydrochlorothiazide fibric acid derivatives, e.g. fenofibrate hypoglycaemic: tolbutamide ' Data from The Medical Letter 1995 37: 35. 305 16 DRUGS AND THE SKIN nonsteroidal anti-inflammatory: piroxicam psoralens (see below). Topically applied substances that can produce photosensitivity include: pam-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 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 photo- chemical 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 photo- chemical reactions in the skin. After topical or systemic administration of the psoralen and sub- sequent exposure to UVA there is an erythematous reaction that goes deeper than ordinary sunburn and that 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 charac- terised by increased epidermal proliferation), and cutaneous T cell lymphoma. Severe adverse reactions can occur with psoralens and ultraviolet radiation, including increased risk of skin cancer (due to mutagenicity inherent in their action), cancer of the male genitalia, cataracts and accelerated skin aging; 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 widely used in an attempt to reverse some of these tissue changes. MISCELLANEOUS SUBSTANCES Keratolytics are used to destroy unwanted tissue, including warts and corns. Great care is obviously necessary to avoid ulceration. They include trichloracetic acid, salicylic acid and many others. Resorcinol and sulphur are mild keratolytics used in acne. Squalane is a saturated hydrocarbon insoluble in water but soluble in sebum. It therefore penetrates the skin and is a vehicle for delivery of agents; it is water repellent and is used for incontinence and prevention of bed sores. It appears in mixed formulations. Salicylic acid may enhance the efficacy of a topical steroid in hyperkeratotoic disorders. Tars are mildly antiseptic, antipruritic and they inhibit keratinisation in an ill-understood way. They are safe in low concentrations and are used in psoriasis. Photosensitivity occurs. There are very many preparations, which usually contain other 306 16 CUTANEOUSADVERSE DRUG REACTIONS substances, e.g. coal tar and salicylic acid ointment; it is sometimes useful to add an adrenal steroid. 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. It is of limited value. 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 (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. About 10% is absorbed. Plainly the vehicle in which they are applied is also important, and an acceptable substance achieving persistence of effect beyond a few hours has yet to be developed. But the alternative of spreading an insecticide in the environment causing general pollution and indiscriminate insect kill is unacceptable. Selective environmental measures against some insects, e.g. mosquitoes, are sometimes feasible. Benzyl benzoate may be used on clothes; it resists one or two washings. the same drug may produce different rashes in different people. Irritant or allergic contact dermatitis is eczematous and is often caused by antimicrobials, local ana- esthetics, topical antihistamines, and increasingly commonly by topical corticosteroids. It is often due to the vehicle in which the active drug is applied, particularly a cream. Reactions to systemically administered drugs are commonly erythematous, like those of measles, scarlatina or erythema multiforme. They give no useful clue as to the cause. They commonly occur during the first 2 weeks of therapy, but some immu- nological reactions may be delayed for months. Patients with the acquired immunodeficiency syndrome (AIDS) have an increased risk of adverse reactions, which are often severe. Though drugs may change, the clinical problems remain depressingly the same: a patient develops a rash; he is taking many different tablets; which, if any, of these caused his eruption, and what should be done about it? It is no answer simply to stop all drugs, though 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 needed but no simple set of rules exists that can cover this complex subject . 8 The following questions should be asked in every case: • Can other skin diseases be excluded? • Are the skin changes compatible with a drug cause? • Which drug is most likely to be responsible? • Are any further tests worthwhile? • Is any treatment needed? These questions are deceptively simple but the answers are often difficult. Cutaneous adverse drug reactions DRUG-SPECIFIC RASHES Despite great variability, some hints at drug-specific Drugs applied locally or taken systemically often cause rashes. These take many different forms and 8 Hardie R A, Savin J A1979 British Medical Journal: 1935, to whom we are grateful for this quotation and classification. 307 16 DRUGS AND THE SKIN or characteristic rashes from drugs taken systemically, can be discerned, as follows: Acne and pustular: e.g. corticosteroids, androgens, ciclosporin, penicillins. Allergic vasculitis: e.g. sulphonamides, NSAIDs, thiazides, chlorpropamide, phenytoin, penicillin, retinoids Anaphylaxis: x-ray contrast media, penicillins, ACE inhibitors. Bullous pemphigoid: frusemide (and other sulphonamide-related drugs), ACE inhibitors, penicillamine, penicillin, PUVA therapy. Eczema: e.g. 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. Continued use of the drug may lead to erythroderma. They commonly occur at about the ninth day of treatment (or day 2-3 in previously exposed patients), although onset may be delayed until after treatment is completed; causes include antimicrobials, especially ampicillin, sulphonamides and derivatives (sulphonylureas, frusemide (furosemide) and thiazide diuretics). Morbilliform (measles-like) eruptions typically recur on rechallenge. Erythema multiforme: e.g. NSAIDs, sulphonamides, barbiturates, phenytoin. Erythema nodosum: e.g. sulphonamides, oral contraceptives, prazosin. Exfoliative dermatitis and 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: e.g. phenolphthalein (laxative self-medication), sulphonamides, quinine (in tonic water), tetracycline, barbiturates, naproxen, nifedipine. Hair loss: e.g. cytotoxic anticancer drugs, acitretin, oral contraceptives, heparin, androgenic steroids (women), sodium valproate, gold. Hypertrichosis: corticosteroids, ciclosporin, doxasosin, minoxidil. Lichenoid eruption: e.g. p-adrenoceptor blockers, chloroquine, thiazides, frusemide (furosemide), captopril, gold, phenothiazines. Lupus erythematosus: e.g. hydralazine, isoniazid, procainamide, phenytoin, oral contraceptives, sulfazaline. Purpura: e.g. thiazides, sulphonamides, sulphonylureas, phenylbutazone, quinine. Aspirin induces a capillaritis (pigmented purpuric dermatitis). Photosensitivity: see above. Pemphigus: e.g. penicillamine, captopril, piroxicam, penicillin, rifampicin. Pruritus unassociated with rash: e.g. oral contraceptives, phenothiazines, rifampicin (cholestatic reaction). Pigmentation: e.g. oral contraceptives (chloasma in photosensitive distribution), phenothiazines, heavy metals, amiodarone, chloroquine (pigmentations of nails and palate, depigmentation of the hair), minocycline. Psoriasis may be aggravated by 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: 9 e.g. anticonvulsants, sulphonamides, aminopenicillins, oxicam NSAIDs, allopurinol, chlormezanone, corticosteroids. Urticaria and angioedema: e.g. penicillins, ACE inhibitors, gold, NSAIDs, e.g. aspirin, codeine. Recovery after withdrawal of the causative drug generally begins in 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 readministration of the drug (challenge) is safe with fixed eruptions, but not with others, particularly those that may be part of a generalised effect, e.g. vasculitis. Patch and photopatch tests are useful in contact dermatitis, for 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. 9 Roujeau C-J et al 1995 New England Journal of Medicine 333:1600 308 [...]... 461^464 Greaves M W, Sabroe R A1998 Allergy and the skin 1 — Urticaria British Medical Journal 316: 1147-1150 Greaves M W, Wall P D 1996 Pathophysiology of itching Lancet 348: 938-940 Gruchalla R S 2000 Clinical assessment of druginduced disease Lancet 356:1505-1511 James M 1996 Isotretinoin for severe acne (A patient's experience.) Lancet 347:1749 Kalka K et al 2000 Photodynamic therapy in dermatology . withdrawn. Some drugs, notably NSAIDs, induce a 'pseudoporphyria', clinically resembling porphyria cutanea tarda and presenting with skin fragility, . adverse reactions, which are often severe. Though drugs may change, the clinical problems remain depressingly the same: a patient develops a rash;