The Pharmaceutical Journal Vol 262 No p357-362
March 13, 1999 Continuing education

ADVERSE DRUG REACTIONS

(12) Drug-induced skin reactions

By By Anne Lee, MPhil, MRPharmS, and John Thomson, MD, FRCP

Other articles in this series:

• Drug-induced cardiovascular disorders (PJ, January 23, 1999, pp113-8)
• Drug-induced sexual dysfunction and infertility (PJ, May 29, 1999, pp780-4)

The skin is the organ most frequently affected by adverse drug reactions. In 1997, 27 per cent of all reactions reported to the Committee on Safety of Medicines featured skin and subcutaneous tissue reactions. In hospital, cutaneous reactions to drugs are thought to occur in up to 3 per cent of medical inpatients.
Virtually all drugs may induce skin reactions. Although they are usually mild, some are serious and potentially life-threatening, such as the Stevens Johnson syndrome and toxic epidermal necrolysis. Drug eruptions can also occur as part of a spectrum of multiorgan involvement. For these reasons, all drug-associated rashes should be carefully evaluated. Drugs may also be implicated in nail abnormalities and disorders of hair growth, which are not considered here.

AETIOLOGY
The cause of skin reactions is often unknown although many have an allergic or toxic basis. Allergic reactions may be independent of dose and can persist long after the causative drug has been withdrawn. In penicillin hypersensitivity reactions, for example, the skin condition may worsen for seven to 10 days after the drug is withdrawn. It is especially important that allergic skin reactions are correctly identified, since subsequent exposure to the same drug could cause a much more severe reaction. In contrast, toxic reactions are dose-dependent and skin symptoms generally resolve fairly soon after the causative agent is withdrawn.
There are several important predisposing factors. Genetic factors may be an important influence; for example, acetylator status may predispose to sulphonamide reactions. The role of atopy in predisposing to drug reactions is controversial. It may be important in reactions to iodinated contrast material but not in reactions to penicillins or reactions during anaesthesia. Patients who have a reliable history of drug allergy always need to be carefully monitored on the initiation of any drug, but particularly those commonly implicated in skin reactions. Hepatic disease, renal disease, systemic lupus erythematosus and AIDS are some of the disease states associated with an increased risk of skin reactions. Drug allergy is more common in the elderly and may be related to the development of an immune response or to increased exposure to drugs. The route of administration can influence drug allergy; in general, topical application has the greatest propensity to induce allergy, followed by parenteral then oral administration.

DIAGNOSIS
It can be difficult to diagnose a drug eruption confidently. Most drugs are associated with a spectrum of skin reactions, and the dictum "any rash, any drug" has been used. A few drugs, however, seldom cause skin reactions; these include digoxin, ferrous sulphate and potassium chloride. Many eactions cannot be distinguished from naturally occurring eruptions so misdiagnosis is common. For example, it may be difficult to differentiate an antibiotic-induced morbilliform eruption from a rash due to concomitant infection and this may unnecessarily limit the future use of a particular medication. Furthermore, patients are often taking more than one drug, making it more difficult to confirm the cause.
The timing of skin reactions is often a useful diagnostic tool. In general, the onset occurs within a short time after the introduction of the causative drug. However, there are important exceptions; the onset of hypersensitivity reactions to penicillins can occur within a few weeks after the drug has been discontinued.
Drugs suspected of causing skin reactions should usually be withdrawn and not used again in that patient. Symptomatic treatment with calamine lotion or systemic antihistamines may be required. For more serious reactions, systemic corticosteroids may be indicated. The main clinical features that are suggestive of a more severe reaction include mucous membrane involvement, blisters or skin detachment, high fever, angioedema or tongue swelling, facial oedema, kin necrosis, lymphadenopathy or dyspnoea.
Although skin prick or blood tests may be used in the diagnosis of some reactions (eg, those dependent on IgE such as immediate-type reactions to penicillin), they are not usually helpful in skin manifestations of an allergy. Skin prick tests can be dangerous and should only be carried out close to intensive care facilities. Rechallenge is seldom indicated in the diagnosis of skin reactions because of the inherent risks.

PHARMACIST'S ROLE
When a skin rash is potentially drug-induced, the pharmacist should take an accurate medication history. All current and recent medication should be noted, including over-the-counter, herbal preparations, and injections, including vaccines or contrast media.
Pharmacists may be more aware than other health professionals of the problems that can occur due to sensitivity to pharmaceutical excipients, which is often manifest as skin reactions. It can be useful to know when each drug was first taken relative to the onset of the reaction and whether there has been previous exposure to the drugs. The patient should be asked whether they have a previous history of drug sensitivity, contact dermatitis, or atopic disease with asthma or eczema. If possible, the rash should be examined to determine whether it appears typical of a classic drug-induced eruption.

EXANTHEMATOUS (ERYTHEMATOUS) REACTIONS

PANEL 1: SOME DRUGS THAT COMMONLY CAUSE EXANTHEMATOUS REACTIONS Antituberculous drugs Barbiturates Carbamazepine Cephalosporins Erythromycin Frusemide Gold Gentamicin Isoniazid Nitrofurantoin Penicillins Phenothiazines Phenylbutazone Phenytoin Sulphonamides Thiazides

The term exanthema is an umbrella term for skin reactions which literally burst forth on the skin. Enanthematous reactions similarly occur on the mucous membranes. Typical characteristics of skin exanthemas include erythema (redness), or morbilliform (resembling measles) or maculopapular lesions. Macules are small, distinct, flat areas and papules are small, raised lesions. This is the most common type of drug-induced cutaneous reaction. The eruption often starts on the trunk; the extremities and intertriginous areas are often involved, but the face may be pared. The rash is usually bright red in colour and the skin may feel hot, burning or itchy.
These reactions can occur with almost any drug at any time up to two to three weeks after starting drug administration, but they are most common within the first 10 days. If the causative drug is continued, exfoliative dermatitis may develop. Occasionally, the eruption subsides despite continuation of the medication. These eruptions usually resolve within a few weeks of discontinuing the causative drug. Ampicillin, amoxycillin and sulphonamides frequently cause these rashes. Drugs that commonly cause exanthematous reactions are shown in Panel 1.

ERYTHRODERMA AND EXFOLIATIVE DERMATITIS
A widespread confluent erythematous rash (erythroderma) often associated with desquamation (exfoliative dermatitis) is one of the most severe patterns of cutaneous reactions to drugs. It may follow exanthematous eruptions or may develop as erythema and exudation in the flexures. There may be systemic symptoms such as fever, lymphadenopathy and anorexia. Possible complications include hypothermia, fluid and electrolyte loss, and infection. The main drugs implicated are sulphonamides, chloroquine, penicillin, phenytoin and isoniazid.

Case study On a Saturday evening just before closing, one of your counter assistants asks if you could speak to Mrs K, a young woman who is obviously anxious about her 14-month-old baby, Matthew. Mrs K has the baby with her. She explains that he is half-way through a prescribed course of amoxycillin for a middle ear infection. Yesterday she noticed that Matthew had developed three or four red blotches on his upper chest and shoulders. She telephoned the local emergency GP service and was advised to use calamine lotion and to continue with the antibiotic. She was asked to get back in touch if the rash became worse. This morning the blotches had seemed much improved. However, when Mrs K came back from work this afternoon she noticed that Matthew had a slight temperature and that the blotches had spread. The baby seems happy enough and is not otherwise unwell. Mrs K is unsure what to do as she does not want to call the doctor out without good reason. The skin rash is now affecting most parts of the body. On examination the lesions are large, deep red, circles which look darker in the centre. There is no sign of blistering or exfoliation. Matthew seems fairly bright but he does seem feverish. What are the most likely possible causes of skin rash in an infant? There are various possible causes, the most obvious of which are viral or bacterial infection (eg, chickenpox, measles), staphylococcal superinfection of eczema or allergy to a chemical or drug. What skin disorder does this type of lesion suggest? The erythematous lesions described are suggestive of the “target-like” lesions which are characteristic of erythema multiforme. Penicillins are a recognised cause of this sort of reaction but infection is also a common cause. The presence of fever could indicate progression to a more serious skin disorder. Is there any other information that might be important? It would be important to ascertain whether the baby has had any other medication recently (eg, OTC cough mixtures, analgesics, vaccinations), exactly how long the antibiotic has been taken, whether there is any history of eczema or drug allergy, and whether there are any other signs or symptoms, particularly mucous membrane involvement (eg, lesions in the mouth). It is also worth finding out what brand of amoxycillin was dispensed so that you can check the constituents for artificial colourings, etc. What advice do you give Mrs K and why? You should tell Mrs K that it is not possible for you to give a diagnosis but that skin rashes like this in children should always be taken seriously. You should explain that the rash might be due to an infection or a side effect of the medication. Mrs K should not give Matthew any more of the antibiotic in the meantime. Because the rash has spread and because Matthew has a temperature, the best course of action would be to call out the doctor immediately or to go to the hospital casualty department.

FIXED DRUG ERUPTION
A fixed drug eruption is the only cutaneous reaction for which drugs are the sole cause. It consists of erythematous round or oval lesions of a dusky purple or brown colour sometimes featuring blisters or vesicles. Initially, one lesion appears although others may subsequently occur. The affected individual may complain of itching or burning in the affected area but systemic involvement is usually absent.

PANEL 2: SOME DRUGS THAT MAY CAUSE FIXED DRUG ERUPTION Barbiturates Carbamazepine Chlordiazepoxide NSAIDs Phenolphthalein Phenylbutazone Quinine Salicylates Tetracyclines Trimethoprim

The eruption generally appears within 24 hours of drug ingestion and can occur on any part of the skin or mucous membranes. The sites most frequently affected are the hands and feet, penis and perianal areas. The site of the eruption is fixed, ie, when the individual takes the causative drug again the eruption generally recurs within eight hours at exactly the same site as was previously affected. Healing occurs over seven to 10 days after the causative drug is stopped although there may be residual hyperpigmentation. The pathogenesis of fixed drug eruption is not well understood. Phenolphthalein is probably the most common cause. Drugs implicated are shown in Panel 2.

URTICARIA AND ANGIOEDEMA
Urticaria and angioedema are physical signs rather than specific diagnoses; both are common features of hypersensitivity reactions. Chronic urticaria may have many different causes or may be idiopathic. Acute urticaria, known as nettle rash or hives, is a common drug reaction, usually occurring within 36 hours of drug exposure. It presents as raised, itchy, red blotches or wheals which may be pale in the centre and red around the outside. Individual lesions rarely persist for more than 24 hours. On rechallenge, lesions may develop within minutes. Management of acute urticaria involves stopping the causative agent and treatment with systemic antihistamines.
Angioedema is a vascular reaction resulting in increased permeability and fluid leakage, leading to oedema of the deep dermis, subcutaneous tissue or submucosal areas. It has a lower incidence than urticaria. The tongue, lips, eyelids or genitalia are generally affected and the oedema may be either unilateral or symmetrical. Angioedema of the upper respiratory tract can result in serious acute respiratory distress, airway obstruction and death. This serious reaction should always be reported to the CSM if drug therapy is a possible cause.

PANEL 3: SOME DRUGS THAT MAY CAUSE URTICARIA/ ANGIOEDEMA ACE inhibitors Anaesthetics (local and general) Antibiotics Dextrans Enzymes (eg, streptokinase) Hydralazine Insulin Muscle relaxants NSAIDs Opioids Radiocontrast media Salicylates

Angioedema is a recognised problem with all angiotensin converting enzyme inhibitors (ACE inhibitors). The estimated incidence is 0.1 to 0.2 per cent in Caucasians but may be higher in other racial groups. In most cases, the reaction has occurred in the first week after starting therapy, often within hours of the initial dose. However, in some cases it has developed after prolonged therapy of up to several years. The mechanism is poorly understood. Drug-induced angioedema is usually mediated by immunological factors. With ACE inhibitors, it has been postulated that bradykinin may be involved, but angiotensin II receptor antagonists can also induce angioedema, even though they do not affect bradykinin. ACE inhibitors should be withdrawn immediately in any patient who presents with angioedema and an appropriate drug of a different class (not an angiotensin II antagonist) substituted. ACE inhibitors are contraindicated in patients with a history of idiopathic angioedema. Panel 3 shows drugs which may cause urticaria or angioedema.

ACNE
Some drugs can cause or exacerbate acne. The term acneiform is applied to drug eruptions that resemble acne vulgaris. The lesions are papulopustular but comedones are usually absent. Corticotrophin (ACTH), corticosteroids, androgens (in females), oral contraceptives, isoniazid and lithium are among the most frequently implicated drugs.

PSORIASIS AND PSORIASIFORM ERUPTIONS
Psoriasiform eruptions typically consist of erythematous plaques surmounted by large dry silvery scales. A number of drugs can induce psoriasis in patients with no previous history or can worsen pre-existing psoriasis, although many reports are anecdotal and causality is unknown.
One fairly definite trigger is lithium which can unveil psoriasis in the susceptible or aggravate existing psoriasis. Several investigators have confirmed that interferon alfa may either induce or worsen psoriasis. The lesions have been shown to improve on withdrawal of interferon and to recur on reintroduction or rechallenge. In patients with pre-existing psoriasis, symptoms usually developed within the first month of treatment but in those with no previous history they developed after at least two months’ treatment. Other interferons have also been implicated.

PANEL 4: SOME DRUGS THAT MAY CAUSE PSORIASIFORM ERUPTIONS OR EXACERBATE PSORIASIS ACE inhibitors Beta-blockers Chloroquine and hydroxychloroquine Granulocyte colony stimulating factor   (GCSF) Gold Interferons Lithium NSAIDs Tetracyclines

The effect of chloroquine and hydroxychloroquine on psoriasis is variable; in some studies, most patients treated noted no change in their condition while, in others, symptoms worsened in a large proportion of patients. It is clear that psoriasis may worsen in some patients and this may make treatment decisions difficult in certain situations. For example, chloroquine may not be an appropriate drug for antimalarial prophylaxis in a patient with psoriasis, depending on the risk of infection in the place to be visited. Care should be taken with the use of hydroxychloroquine in patients with psoriatic arthropathy.
Over the past 20 years, skin eruptions have been described with numerous b- blockers. Practolol was withdrawn in the UK following a serious syndrome termed the oculomucocutaneous syndrome, featuring a psoriasiform rash, xerophthalmia due to lachrymal gland fibrosis, otitis media, sclerosing peritonitis and a lupus-like syndrome. The pathogenesis of this adverse effect remains unknown, but it appears to have been unique to practolol. Psoriasiform eruptions have since been reported with cardioselective and non-cardioselective beta-blockers. Ophthalmic preparations (eg, timolol) have also been implicated. Cross-reactivity has been noted among propranolol, oxprenolol and atenolol. Beta-blockers may also transform psoriasis into pustular psoriasis or erythrodermatous psoriasis. The time to onset of the reaction can vary between days to up to a year after initiation of therapy. The underlying mechanism is unknown but b2 receptors are found in the epidermis. Psoriasis induced by b-blockers is reported to be resistant to antipsoriatic therapy until the b-blocker has been stopped.

PURPURA
Purpura describes small cutaneous extravasations of blood. The main causes are thrombocytopenia, platelet dysfunction, or cutaneous or vascular disease. Drug-induced skin eruptions occasionally feature purpura and purpura is the main feature in some cases. There is no reliable physical sign that helps to distinguish thrombocytopenic from non-thrombocytopenic purpura. Drugs commonly implicated in vascular purpura include aspirin, quinine, sulphonamides, atropine and penicillin.

VASCULITIS

PANEL 5: SOME DRUGS FREQUENTLY IMPLICATED IN VASCULITIS Allopurinol Ampicillin Cimetidine Frusemide Granulocyte colony stimulating factor   (GCSF) Hydralazine NSAIDs Phenytoin Propylthiouracil Sulphonamides Thiazides

Vasculitis results in inflammation and necrosis of blood vessel walls. Drugs are thought to cause about 10 per cent of acute cutaneous vasculitis. The mechanism is believed to be immune complex mediated. Vasculitis commonly presents with raised purpuric (purple) lesions on the legs. Urticarial lesions, ulcerated areas and haemorrhagic blisters may also be present. The lesions range in size from a pinpoint to several centimetres. Vasculitis typically develops seven to 21 days after the initiation of a new drug. The skin lesions may persist for one to four weeks or longer and in some cases become yellow to brown upon healing. Systemic symptoms, such as malaise, arthralgia and fever, may be present. Drug-induced vasculitis may also involve other organs, including the heart, liver and kidneys.
Drug-induced vasculitis is difficult to diagnose. Other causes to eliminate include Henoch-Schonlein purpura in young patients, cryoglobulinaemia, polyarteritis nodosa, infection and collagen vascular disease. Management involves stopping the suspect drug promptly. Systemic corticosteroids may be of some benefit in severe reactions.
Panel 5 shows drugs implicated in vasculitis.

ERYTHEMA MULTIFORME
Erythema multiforme (EM) is a cutaneous response triggered by various infections and drugs (see Panel 6). As the name implies, it can present with a variety of patterns. The classic pattern affects the hands and feet more than the trunk. There may be blisters, papular lesions or erythematous areas. A characteristic lesion is one of concentric rings, variously described as target, iris or bullseye shaped.

PANEL 6: SOME DRUGS THAT MAY CAUSE ERYTHEMA MULTIFORME OR STEVEN JOHNSON SYNDROME Barbiturates Carbamazepine Cimetidine Co-trimoxazole Chlorpropamide Gold Lamotrigine NSAIDs Penicillins Phenothiazines Phenytoin Rifampicin Sulphonamides Tetracyclines Thiazides

Involvement of the mucosa is common, so the mouth, eyes and genitalia may be affected.
Infections are a more common cause of EM than drugs and many cases have been wrongly blamed on drugs. Erythema multiforme may be due to vaccination, a variety of topical medications, and some environmental substances (eg, nickel). When the condition is suspected, all drugs, especially those introduced within the past month, should be discontinued, since there is a risk of progression to Stevens Johnson syndrome or toxic epidermal necrolysis.

STEVENS JOHNSON SYNDROME
Stevens Johnson syndrome (SJS) comprises fever, malaise, myalgia, arthralgia, and extensive erythema multiforme of the trunk and face. It is frequently drug induced. There may be skin blistering and erosions covering less than 10 per cent of the body’s surface area. This syndrome is distinct from toxic epidermal necrolysis (TEN) but there is a degree of overlap as severe forms of SJS can evolve into TEN and several drugs can produce both entities. The estimated incidence of SJS ranges between 1.2 and 6 per million population per year. In about 50 per cent of cases the cause is not known. The fatality rate is believed to be about 5 per cent.
A large number of drugs has been implicated as a cause of SJS. Penicillins, tetracyclines, sulphonamides and NSAIDs are among the most common. Patients with HIV infection seem to be at increased risk of developing SJS with co-trimoxazole. Drugs that may be responsible for the reaction should be stopped immediately. Management involves systemic corticosteroids, fluid replacement and antibiotics, if required. Drug rechallenge is never justified.

TOXIC EPIDERMAL NECROLYSIS
Toxic epidermal necrolysis (TEN), or Lyell’s syndrome, is a rare variety of erythema with acute epithelial necrosis affecting all areas of the skin. The estimated incidence ranges from 0.4 to 1.2 per million population per year. It has a high associated mortality of about 30 per cent. In TEN, sheet-like skin erosion affects more than 10 per cent of the body surface and there is severe involvement of the mucous membranes (oropharynx, eyes and genitalia). The main cause in adults is drugs. Patients with HIV infection, systemic lupus erythematosus and bone marrow transplant recipients seem to be predisposed to this disorder. Elderly patients and those with extensive TEN have a worse prognosis. Drug-induced TEN is rare in children, in whom the diagnosis must be distinguished from staphylococcal “scalded skin syndrome.”
TEN presents with a prodromal period of fever, conjunctivitis, pharyngitis, pruritus and, occasionally, difficulty in urination. These symptoms generally last two to three days and can resemble an upper respiratory tract infection. The burning or painful skin rash generally begins on the face or upper trunk and is characterised by poorly defined erythematous or dark coloured macules, irregular target-like bullae, or diffuse ill-defined erythema. The affected skin may develop flaccid bullae or may detach irregularly, sometimes in large sheets. The lesions generally progress and extend in waves over a three to four day period, but can progress rapidly in a few hours, or more slowly. In most cases, mucosal lesions are present, particularly of the buccal mucosa, with the ocular and genital mucosa affected less often. The consequences of such a massive loss of epidermis include dehydration, increased energy expenditure, and local or systemic infection such as septicaemia. In severe cases, other organ systems can be involved: hepatocellular damage, pneumonia, nephritis and myocardial damage may occur. Skin sloughing can extend into the oesophagus and bronchial tree.

PANEL 7: SOME DRUGS THAT MAY CAUSE TOXIC EPIDERMAL NECROLYSIS Allopurinol Barbiturates Carbamazepine Gold Griseofulvin Lamotrigine Nitrofurantoin NSAIDs (especially oxicam derivatives) Penicillins Phenytoin Salicylates Sulphonamides Tertacyclines

The mechanisms responsible for TEN are unknown although a hypersensitivity- immunological basis is suspected. A TEN-like eruption has occurred in patients with a graft-versus-host reaction after bone marrow transplant.
Identification of the causative drug is often difficult. In general, most drugs causing TEN have been given in the previous one to three weeks. A drug is unlikely to be the cause if it was first given in the preceding 24 hours or if it has been taken for more than three weeks. However, phenytoin-induced TEN can occur at any time between two and eight weeks after initiation of therapy and may progress despite discontinuation of the drug.
There is some debate about where this serious condition should be managed. It has been suggested that management in a specialist burn units is preferred. Treatment involves the careful protection of exposed dermis and eroded mucosal surfaces, managing fluid and electrolyte balance, nutritional support, and close monitoring for evidence of infection. Antibiotic therapy should be reserved for treatment rather than given prophylactically. The place of systemic corticosteroids is controversial.
The Committee on Safety of Medicines has recently warned about the risk of serious skin reactions with the antiepileptic lamotrigine. About 1 in 1,000 adults develop these reactions, including Stevens Johnson syndrome and toxic epidermal necrolysis. Children appear to be at increased risk and the frequency of these problems may be as high as 1 in 300 to 1 in 100. Factors associated with an increased risk of skin reactions include the use of higher than recommended doses, more rapid dose escalation than recommended, and concomitant use of valproate. Most of these problems have developed within eight weeks of starting lamotrigine and resolved upon withdrawal but deaths have occurred.

PEMPHIGUS-LIKE ERUPTIONS
Idiopathic pemphigus and bullous pemphigoid are autoimmune disorders. Idiopathic pemphigus typically features superficial blisters, although sometimes erythema, crusting and scaling are the major clinical signs. Idiopathic bullous pemphigoid is characterised by large blisters developing on an erythematous base. A number of drugs, most of which contain a thiol (or sulphydryl) group in their molecular structure, has been implicated in causing a disorder closely resembling these idiopathic conditions (Panel 8). Cicatricical pemphigoid is a rare variant in which mouth ulcers, eye problems and other complications may develop, with subsequent scarring.

SOME DRUGS THAT MAY CAUSE PEMPHIGUS-LIKE ERUPTIONS Captopril Enalapril Flupenthixol Frusemide Interleukin-2 Penicillamine Penicillins Sulphasalazine

The drug-induced disorder has a broad spectrum of clinical presentation comprising widely scattered large, firm, bullae, classical but fewer lesions, scarring plaques, an erythema multiforme-like picture and a pemphigus-like picture. In general, affected patients are younger than those with idiopathic disease. The drug-induced variant can feature clinical characteristics of both pemphigus and pemphigoid. The mechanism is unknown; both immune and toxic mechanisms have been proposed.
The entire clinical spectrum of pemphigus has been reported in association with penicillamine. As many as 7 per cent of patients taking the drug for more than six months develop a pemphigus-like eruption. This is thought to be a cutaneous manifestation of the autoimmunogenic properties of the drug. Evidence suggests that the penicillamine-induced variant of pemphigus is essentially the same as the idiopathic condition. The disease usually improves when penicillamine is stopped but may persist for many years and recur on rechallenge.

PHOTOSENSITIVITY

Photosensitivity denotes a reaction occurring when a photosensitising agent in or on the skin reacts to normally harmless doses of ultraviolet or visible light. It can be caused by topical or systemic drugs (see Panel 9). Drug-induced photosensitivity is classified as either phototoxic or photoallergic.

PANEL 9: SOME DRUGS ASSOCIATED WITH PHOTOSENSITIVITY Frequent Amiodarone NSAIDs Phenothiazines (particularly   chlorpromazine) Retinoids Sulphonamides Tetracyclines (particularly   demeclocycline) Thiazides Less frequent Antidepressants (tricylic, MAOIs) Carbamazepine Griseofulvin Quinolones Quinine Sulphonylureas

Phototoxic reactions Phototoxic reactions are common and can be produced in most individuals given a high enough dose of drug and sufficient light exposure. The eruption is usually evident within 5-20 hours of exposure and resembles an exaggerated sunburn with erythema, oedema, blistering, weeping and desquamation. The rash is confined to areas exposed to light. Hyperpigmentation may remain after other features have subsided. Patients taking potent photosensitising agents should be warned of the problem and counselled on the need to avoid direct sunlight and to use sunblocks.
Amiodarone therapy is associated with a 30-50 per cent incidence of photosensitivity. Symptoms develop within two hours of sun exposure as a burning sensation followed by erythema. A minority of affected patients develop a slate-grey pigmentation on light exposed areas. Light sensitivity may persist for up to four months after the drug is stopped. Cutaneous pigmentation slowly fades after amiodarone is stopped but may persist for months to years. The problem is related to both the dosage and duration of drug therapy. Skin cells and cells of other organs in affected patients have been found to contain myelin-like lysosomal structures and membrane-bound granules. This generalised derangement of lysosomal storage may also be the basis for other adverse effects of amiodarone such as interstitial alveolitis, acute hepatitis and disturbed thyroid function.
Chlorpromazine may cause a phototoxic response when given in high dose. The reaction is characterised by a burning, painful erythema within minutes of exposure to sunlight, either directly or through window panes. Erythema may persist for more than 24 hours. Occasionally, a golden-brown or slate-grey pigmentation, predominantly of exposed sites, may be seen. Photoallergy is less common than phototoxicity and may occur following exposure to chlorpromazine powder.

Photoallergic reactions Photoallergic reactions occur in predisposed individuals who have been previously sensitised. There is a latent period during which sensitisation occurs and the reaction generally develops within 24 hours of re-exposure. Unlike phototoxic reactions, the reaction may spread beyond irradiated areas. Most systemic drugs causing photoallergy also cause phototoxicity.
These reactions may occur as a result of local photocontact dermatitis to a topical photoallergen or a result of systemic drug therapy.

LICHENOID DRUG ERUPTIONS

PANEL 10: SOME DRUGS THAT MAY CAUSE LICHENOID ERUPTIONS Antimalarials Beta-blockers Captopril Gold Interferon alfa Lithium Methyldopa NSAIDs Penicillamine Sulphonylureas

Lichenoid drug eruptions (LDE) are so called because of their resemblance to idiopathic lichen planus. The first drugs reported to cause lichenoid skin reactions were arsenicals used in the treatment of syphilis. Several causative drugs are now known (Panel 10) although LDE is quite rare in comparison with other drug-induced skin reactions. The lesions can be described as small, shiny, polygonal papules, sometimes with characteristic white lines known as Wickham’s striae. They are usually itchy but they can be asymptomatic. The surrounding skin is completely normal. LDE can rarely affect the buccal mucosa; a characteristic white lace pattern may be present.
Lichenoid drug eruptions tend to be extensive and may be linked with, or develop into, an exfoliative dermatitis. LDE can also result from contact dermatitis in photographic workers who handle certain p-phenylenediamines.
The clinical course of LDE has been investigated in many studies. The mechanism is thought to have an immunological basis. The time to onset of the reaction ranges from weeks to months after initiation of therapy. In most patients the symptoms cleared spontaneously within a few weeks of drug withdrawal. In prolonged or severe cases, topical or systemic corticosteroids may be used.

A fully referenced copy of this article is available on request. Please send an A4 stamped and addressed envelope to: The Pharmaceutical Journal, 1 Lambeth High Street, London SE1 7JN.

FURTHER READING 1. Breathnach SM, Hintner H. Adverse drug reactions and the skin. Oxford: Blackwell Scientific Publications, 1992. 2. Smith AG. Important cutaneous adverse drug reactions. Adverse Drug Reaction Bulletin 1994;167:631-4. 3. Nowakowski PA, Rumsfield JA, West DP. Drug-induced skin disorders. In: Dipiro JT, Talbert RL, Yee GC, et al, editors. Pharmacotherapy: a pathophysiologic approach. 3rd ed. Appleton & Lange: Connecticut, 1997. 4. Ryan TJ. Diseases of the skin. In: Weatherall DJ, Ledingham JGG, Warrell DA, editors. Oxford textbook of medicine. 3rd ed. Oxford: Oxford University Press, 1995. 5. Magee P. Drug-induced skin disorders. In: Walker R, Edwards C, editors. Clinical pharmacy and therapeutics. 2nd ed. Edinburgh: Churchill Livingstone, 1999.

Mrs Lee is principal pharmacist, area drug information centre, Glasgow Royal Infirmary, and Dr Thomson is consultant dermatologist, Glasgow Royal Infirmary