Drug-induced photosensitivity can be either phototoxic or photoallergic (Box 56.1). Phototoxic reactions, which are more common, resemble severe sunburn and can progress to blistering. They are dose dependent for both the drug and sunlight, occur within 5–15 h of taking the drug and subside quickly on drug withdrawal. Photoallergic rashes are usually eczematous, but may be lichenoid, urticarial, bullous or purpuric. They are not dose dependent and occur following exposure to normal amounts of sunlight exposure. The onset can be delayed by weeks or months, while recovery is often slow following drug withdrawal. Rarely, a photoallergic state can persist for years after the drug responsible has been discontinued.

Patients receiving known photosensitising drugs should be advised to avoid strong sunlight. They should also be advised to use a broad-spectrum topical sunscreen, providing both UVA protection (indicated by the ‘star rating’ on the bottle) and UVB cover (indicated by the sun protection factor, SPF).

Pigmentary changes

The skin’s colour can be altered by drugs: hyper-pigmentation, hypo-pigmentation and discoloration can all potentially be induced by a variety of medicines (see Fig. 56.1 and Table 56.1). Pigmentary changes can be widespread or localised. The most common examples of localised pigmentation are the facial blue–black pigmentation in individuals on amiodarone or minocyline, and melasma facial pigmentation occurring in some women taking the combined oral contraceptive pill. Generalised pigmentary change induced by drugs is rare, but can occur with chemotherapeutic agents such as bleomycin. This may have the appearance of generalised hyper-melanosis, or may take on a more flagellate appearance with multiple linear areas of hyper-pigmentation.

Fig. 56.1 Minocycline pigmentation: this female patient was taking minocycline for 2 years for treatment of rosacea and developed unsightly grey pigmentation round the mouth. This did not respond to stopping the medication.

Table 56.1 Drugs causing skin pigmentation

Drug	Pigmentation
Amiodarone	Blue-Grey
Anticonvulsants	Brown
Antimalarials	Blue-Grey
β-Blockers	Brown
Imatinib	Hypo/Hyperpigmentation
Imipramine	Blue/Grey
Mepacrine	Blue/black
Methyldopa	Brown
Oral contraceptives	Brown spots/patches
Phenothiazines	Brown/Blue-Grey
Psoralens	Brown
Tetracyclines	Blue-Black

The mechanism of drug pigmentation is not always known; however, proposed pathogenetic mechanisms are:

(1) Drug or drug metabolite deposition in the dermis and epidermis. An example of this would be agyria, in which systemic absorption of silver from, for example, topical silver sulphadiazine, causes a slate-grey discolouration of the skin.

(2) Enhanced melanin production with or without an increase in the number of active melanocytes. This appears to be the pathogenetic mechanism in melasma and also bleomycin-induced pigmentation (Moncada et al., 2009)

Nail changes

The growth and colour of finger and toenails can be modified by drugs. Abnormalities of texture and architecture of the nail unit can also be drug-induced. Blue discoloration of the nails can result from therapy with mepacrine, while a blue–black pigmentation may accompany treatment with minocycline and certain cytotoxic drugs such as hydroxyurea. Potassium permanganate solutions will dye nails brown. White nails (leuconychia) can result from treatment with chemotherapy agents, especially, cyclophosphamide, doxorubicin and vincristine. Beau’s lines, transverse depression of the nail, represent interruption to the normal growth of the nail matrix, and are caused by systemic infection, metabolic upset, or occasionally by drugs. In the drug-induced form, the most common cause is again chemotherapy agents, similar to those which cause leuconychia.

Onycholysis is characterised by separation of the nail plate from the underlying nail bed. Any cytotoxic agent may induce onycholysis by direct toxicity to the matrix. Photo-onycholysis describes lifting of the nail plate and is caused by the combination of a photosensitising drug, for example minocycline, oxytetracycline and UVA exposure.

Hair changes

Drugs may exert an effect on the hair follicle itself or on the growth cycle of hair. The cycle of hair growth involves anagen (the growth phase of the hair), catagen (the resting phase) and telogen (the shedding phase). Either loss of hair or excessive growth of hair may result.

Loss of hair

Drug-induced alopecia (Box 56.2) may be partial or complete. The temporal relationship between the introduction of the drug and the subsequent loss of hair depends on the part of the hair cycle with which the drug interferes. Cytotoxic drugs interfere with the ‘anagen’ or growth phase of the hair cycle, and so loss is rapid and complete; it begins shortly after administration of the drug and the effect is dose dependent and fortunately reversible, but a delay of several weeks is common before regrowth begins.

Delayed hair loss following the introduction of a drug is a more insidious process and may not be noticed immediately by the patient. In this scenario, the drug is often interfering with the ‘telogen’ or shedding part of the hair cycle, moving follicles through this phase more quickly. Hair is shed at a rate that exceeds that at which the follicles can produce new hair, resulting in a thinning effect. Given the length of the hair cycle, this type of hair loss can occur 2–4 months after a drug is initiated. Retinoid therapy, including isotretinoin prescribed for acne, or acitretin for psoriasis, may induce a telogen alopecia.

Androgens promote shrinking of hair follicles and shorten duration of the growth stage of the hair-follicle cycle (anagen stage). Drugs with androgen activity can induce male-pattern baldness, for example exogenously administered testosterone, which may be prescribed for hypogonadism in men and occasionally in post-menopausal women as an adjunct to hormone replacement therapy. Oestrogens are known to prolong the anagen stage and counteract androgenetic alopecia. Oestrogenic stimuli may cause the hair follicle to shift into anagen phase and vice versa. Use of the oestrogen receptor antagonist tamoxifen in women with breast cancer can exacerbate female pattern hair loss. Tamoxifen competes for the oestrogen receptor and produces an environment with relative hyperandrogenism, which may augment the androgen action on follicles.

Excessive hair

Hirsutism is excessive hairiness, especially in women, in the male pattern of hair growth, while hypertrichosis is the growth of hair at sites not normally hairy. Both conditions can be drug induced and in some cases the same drug can produce both patterns of hair growth (see Box 56.2). The capacity of minoxidil to produce hypertrichosis was noted during early trials of this drug as an antihypertensive. It is infrequently used for its originally intended purpose, as it produces profound postural hypotension, but its most noticeable side effect has been exploited as a topical preparation for the treatment of male pattern baldness.

Changes to the skin’s immune system and skin malignancy

The skin’s innate immune surveillance system detects and repairs UV-induced DNA damage thus limiting the tendency to cutaneous carcinogenesis. Drug-induced immunosuppression places an individual at an increased risk of skin cancer, notably squamous cell and basal cell carcinomas. As well as a reduction in immune surveillance, immunosuppression increases susceptibility to the human papilloma virus, some strains of which may predispose to the development of squamous malignancy. Patients taking drugs such as azathioprine, ciclosporin, tacrolimus, mycophenolate mofetil and chemotherapeutic agents should be counselled about the importance of sun protection to minimise the risk of development of malignant and pre-malignant skin cancers. Certain high-risk patients on immunosuppressant drugs, particularly renal transplant recipients, should undergo formal follow-up with skin monitoring by a dermatologist on a yearly basis.

Mild drug-induced skin disorders

Mild drug reaction patterns in the skin are numerous; some of the more commonly seen morphologies are discussed in this section.

Drug-induced exanthems

A drug-induced exanthem (widespread rash) is the most common type of drug reaction in the skin. Exanthems are characterised by erythema (redness) and may be morbilliform (resembling measles) or maculopapular (a mixture of flat and raised areas) (see Fig. 56.2). Less frequently there may be blisters, which may be small (vesicles) or larger (>5 mm, bullae), and the skin may feel hot, burning or itchy.

Fig. 56.2 Drug exanthem: maculopapular, itchy eruption appeared 4 days following the introduction of a course of co-amoxiclav for a respiratory tract infection. Note the linear marks indicating excoriation (scratching) on the left posterior shoulder.

The proportion of the body surface area (BSA) involved varies from case to case but when severe, involving more than 90% of the BSA, the presentation is referred to as ‘erythroderma’, which is discussed later. In theory, any drug is capable of producing a drug-induced exanthem in the skin, but in practice, common causes include antibiotics (e.g. sulphonamides, ampicillin, isoniazid), anticonvulsants (e.g. phenytoin, carbamazepine) and antimalarials (chloroquine).

Most drug-induced exanthems begin within 7 days of commencing a drug, the mechanism being a delayed (type IV) hypersensitivity (Burns et al., 2004). If the drug can be identified, it should be stopped, appropriate symptomatic relief instituted with antihistamines and topical steroids. A clear record of the reaction should be made in the patient’s notes. Both the patient and his primary care doctor should be made aware of the reaction for the purposes of future avoidance.

An exanthematous reaction commonly occurs following administration of ampicillin (or its derivatives, including amoxicillin) to patients suffering from glandular fever (infectious mononucleosis). It does not usually represent a true penicillin allergy, but a complex interplay between viral factors (infectious mononucleosis being caused by Epstein Barr virus) and drug epitopes (Burns et al., 2004). This reaction to the drug would not be expected to be seen in the same patient in the absence of the virus.

Urticaria and angioedema

Urticaria, also known as hives, describes the appearance of red, itchy weals on the skin (Fig. 56.3). Angioedema is a more serious, related condition in which the patient develops deep soft-tissue swellings, mostly notably on the face. Urticaria and angioedema can be either allergic, a reaction between an antigen and specific mast cell-bound IgE, or non-allergic. Drugs are recognised triggers of urticaria and angioedema (Box 56.3) and can also exacerbate pre-existing urticaria. The most important culprits are the NSAIDs and opiates, both of which lower the threshold for mast cell degranulation. ACE inhibitors and angiotensin receptor blockers (ARBs), for example candesartan, can provoke angioedema in a susceptible individual.

Fig. 56.3 Urticaria: patient developed the classic raised red itchy weals of urticaria following the commencement of ibuprofen for musculoskeletal pain.

Drug-induced urticaria/angioedema can be a cutaneous manifestation of anaphylaxis, and in this situation, urgent medical attention is needed with administration of adrenaline, antihistamine and intravenous corticosteroid.

Pruritus

Pruritus (itching) can accompany a drug rash, or may be an isolated symptom provoked by a medication. The most common trigger of drug-induced pruritus is the administration of opiate analgesics and their related synthetic derivatives such as tramadol. Opiate-induced pruritus is centrally mediated, rather than by peripheral nerves; therefore, antihistamines do not, in general, ameliorate the itch. This can pose a particular problem in the palliative care setting where opiate analgesics are required regularly.

Fixed drug eruptions

Fixed drug eruption is characterised by one or more inflammatory patches that recur at the same cutaneous or mucosal site(s) each time the patient is exposed to the offending drug (Fig. 56.4). The eruption usually involves the torso, hands, feet, face or genitalia, and is characterised by a deep red, circular, well-demarcated patch. They take between 2 and 24 h to develop following drug ingestion. On the first drug exposure, there is usually only one lesion, but subsequent exposure can result in multiple lesions.

Fig. 56.4 Fixed drug eruption: female patient developed persistent macular inflamed areas on her upper chest wall 2 months after starting a new combined oral contraceptive pill. A fixed drug eruption was suspected and the lesions resolved after stopping the medicine.

The group of drugs with the potential to cause a fixed drug eruption is virtually limitless, but some of the drugs more commonly responsible are listed in Box 56.4.

Box 56.4 Drugs causing fixed drug eruptions

Once the drug has been stopped, the lesions resolve and may leave an area of post-inflammatory hyperpigmentation. This may be the only physical sign at the time the patient presents. Topical steroids may ameliorate the symptoms.

Acneiform eruptions

Acne may be drug-induced or drug-exacerbated. One of the most commonly prescribed drugs to produce an acneiform eruption is corticosteroid, in either topical or oral form. Illicit use of anabolic steroids by athletes can also produce this effect, occasionally in its most severe form, acne fulminans. Other drugs which may worsen or provoke acne include ciclosporin, lithium and progesterone-only oral contraceptives.

A new class of anticancer drug, endothelial growth factor receptor antagonists, for example cetuximab, commonly produce an acneiform eruption. The papules and pustules which occur are more monomorphic than those seen in idiopathic acne. Interestingly, studies have shown that there is a positive correlation between the severity of the acneiform eruption and response of the cancer to the treatment (Saltz et al., 2003; Susman, 2004) Most drug-induced or drug-exacerbated acne can be managed with the same treatments as used in idiopathic acne, such as topical agents, oral tetracycline antibiotics, erythromycin, or in severe cases, oral retinoids. Examples of drugs which may cause an acneiform eruption are given in Box 56.5.

Psoriasiform eruptions

Drugs can either exacerbate psoriasis in predisposed patients or induce psoriasiform rashes in previously unaffected patients (see Box 56.6). The psoriasiform eruptions mimic psoriasis and are characterised by itchy, scaly red patches on the elbows, forearms, knees, legs and scalp. Drugs which have a well-established effect of worsening pre-existing psoriasis include β blockers, lithium, antimalarials and ACE inhibitors.

Lichenoid eruptions

Drug-induced lichenoid eruptions (see Box 56.7) resemble lichen planus, occurring as flat mauve lesions. However, they may be atypical, showing scaling and confluence. The lesions can be seen at any site, but are found mainly on the forearms, neck and on the inner surface of the thighs. The eruption resolves with drug withdrawal, with or without topical steroids, but post-inflammatory hyperpigmentation is often long lasting.

Eczematous eruptions and contact dermatitis

Retinoid drugs (such as isotretinoin, acitretin and alitretinoin) and statins have a drying effect on the skin, and can exacerbate pre-existing eczema or precipitate eczema in a susceptible individual. Irritant contact dermatitis may be seen in preparations with an alcohol base, such as topical antibiotics, or with the application of topical preparations which are inherently irritant such as benzoyl peroxide, tar or dithranol.

Allergic contact dermatitis is a delayed (type IV) hypersensitivity reaction which can develop to any topical preparation, for example eye drops in a sensitised individual. Most commonly, this will be to excipients contained in the preparation, such as preservatives, for example sodium metabisulphite, fragrances or stabilisers, but may be to the drug itself. In all cases of irritant or allergic contact dermatitis, the patient should be counselled to stop the preparation. Patch testing carried out by a dermatologist is a useful way of investigating patients in whom a diagnosis of allergic contact dermatitis is suspected.

Erythema nodosum

Erythema nodosum is an acute inflammatory reaction with painful subcutaneous nodules, usually but not exclusively found on the shins. Erythema nodosum is usually a complication of infection with, for example, streptococcus or tuberculosis, or is a cutaneous manifestation of an inflammatory condition such as sarcoidosis. In its drug-induced form, it may be caused by oral contraceptives, sulphonamide antibiotics, salicylates, penicillins and gold salts.

Severe drug-induced skin disorders

Erythema multiforme (EM), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are all idiosyncratic, immunologically mediated severe drug eruptions. For our purposes, these diseases may be considered to be on a spectrum, from the mild and self-limiting at one end (EM) to the fulminating severe at the other (TEN).

Erythema multiforme

EM is an eruption of target-like lesions which are characterised by concentric red and pale rings with, in severe cases, central blistering. EM typically occurs on the limbs rather than the trunk but mucous membrane surfaces, such as the eye, the mouth and the genital tract, may also become involved. A significant proportion of EM cases are caused by infection, particularly herpes simplex virus reactivation; however, in some patients, EM is triggered by a drug (see Box 56.8). Drug-induced EM will usually present within 2 weeks of starting a new medication. Once the responsible drug has been stopped, treatment is symptomatic with paracetamol, topical steroids and appropriate topical therapy for the mouth and other involved mucosal surfaces.

Stevens–Johnson syndrome and toxic epidermal necrolysis

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are terms used to describe a life-threatening, mucocutaneous drug hypersensitivity syndrome characterised by blistering and epidermal sloughing (Fig. 56.5). In SJS, there is epidermal detachment of <10% BSA, in TEN there is detachment of >30% of the BSA, while cases with 10–30% involvement are labelled SJS/TEN overlap. The systemic problems which accompany widespread epidermal loss such as high losses of heat and fluid, and the heightened risk of infection due to diminished barrier function can cause serious morbidity, similar to extensive burns. TEN carries a mortality rate of approximately 30%, but this can rise to 90% mortality in the presence of co-morbidities. HIV-infected patients and patients with systemic lupus erythematosus (SLE) have an enhanced risk of developing SJS/TEN. Drugs causing SJS/TEN are listed in Box 56.9.

Fig. 56.5 Stevens–Johnson syndrome is a serious, idiosyncratic reaction of the skin and mucous membranes to a drug. It results in blistering and subsequently widespread epidermal loss and can have a high mortality rate.

Clinical features

A prodrome of fever, malaise, and upper respiratory tract symptoms may precede the eruption by a few days. Involvement of the mucous membranes of the eyes, mouth, and nose is a prominent early feature. Eye involvement results in blepharitis, haemorrhagic conjunctivitis, mucus secretion, and pseudomembranes. Ophthalmological input is required early if long-term sequelae such as blindness from corneal opacities and synechiae are not to occur. Urethral involvement must also be anticipated and the patient catheterised if strictures are not to complicate the disease course. Mouth involvement causes an erosive and haemorrhagic mucositis. On the skin, dusky red macules 1–3 cm in diameter appear at any site and evolve to become confluent. The skin lesions pass through vesicular and bullous phases before epidermal detachment occurs. Shearing pressure to the skin causes detachment of involved epidermis (positive Nikolsky’s sign). In TEN, there is widespread epidermal loss and sloughing of the necrotic epidermis which peels back to leave large areas of exposed dermis. Denuded dermis exudes serum, becomes secondarily infected and readily bleeds. The patient is in severe pain and is usually extremely ill. The visceral manifestations that result from widespread epithelial loss include pneumonia, pancreatitis, thromboembolic disease, renal and hepatic impairment.

The patient with SJS/TEN will require full supportive care, preferably in an intensive care unit. Patients with SJS with less extensive involvement may be managed in a lower-dependency environment, but should be monitored closely for signs of progression in the first 48 h of admission. A multidisciplinary approach, including dermatologists, ophthalmologists and intensive care physicians, is critical to a successful outcome. Following drug withdrawal, the management is supportive, including prompt treatment of infection, careful attention to thermoregulation, fluid balance and skin care, and introduction of appropriate eye and lid care. The literature has failed to identify one treatment which definitively improves outcomes, but agents which have been used include systemic steroids, ciclosporin and intravenous immunoglobulin.

Drug Reaction with Eosinophilia and Systemic Symptoms

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is sometimes known as Drug-Induced Hypersensitivity Syndrome (DIHS) and is a distinct, severe and potentially fatal drug-induced skin disorder. The drugs commonly associated with this syndrome are listed in Box 56.10.

Typically, the dermatosis of DRESS is an extensive, inflammatory, maculo-papular exanthem. Other skin signs may also be present including pustules, purpura, blisters, target-like lesions and facial oedema (Fig. 56.6). To meet the diagnostic criteria, there will also be a haematological abnormality, either a raised eosinophil count (>1.5 × 10⁹/L) or the presence of atypical lymphocytes on the blood film. There is prominent systemic involvement in DRESS, most commonly fever, lymph node enlargement and liver function abnormalities. Less typically, there is renal, pulmonary or cardiac involvement.

Fig. 56.6 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): female patient developed a severe systemic reaction following commencement of phenytoin for seizure prophylaxis after brain surgery. She had an erythematous urticated eruption as seen above accompanied by lymphadenopathy, derangement of liver function, and a circulating eosinophilia.

DRESS is characterised by its long latency of onset with the syndrome usually presenting between 2 and 8 weeks after commencement of the causative drug. This is an important point to note in the medication history, as often the drug responsible may be overlooked if it is considered to have been started ‘too long ago’.

DRESS is accompanied by significant morbidity while the mortality has been estimated at 10%. Systemic steroids are usually administered, and may be beneficial, but there are no randomised controlled trials to support use. Management involves stopping the suspected drug, and supportive care dictated by extent of involvement.

Acute Generalised Exanthematous Pustulosis

Acute Generalised Exanthematous Pustulosis (AGEP) describes a reaction pattern to a drug consisting of widespread sterile, monomorphic pustules studding the skin in a generalised fashion. Such patients are generally systemically unwell with a fever and the complications of generalised skin inflammation including excessive heat and fluid loss. The differential diagnosis would include pustular psoriasis. Although the condition is self-limiting, potent topical steroids may accelerate resolution. The drugs which can cause AGEP are summarised in Box 56.11.

Erythroderma and exfoliative dermatitis

Erythroderma is the term used to describe any pattern of drug reaction in the skin where more than 90% of the BSA is involved. This is usually an extension of a severe drug-induced exanthem. The erythrodermic patient often feels shivery and may have lymphadenopathy and fever. The large surface area involved in erythroderma leads to substantial losses of heat and fluid from the body. This puts the patient at risk of electrolyte imbalances, hypothermia, and with the loss of skin barrier function, infection. Admission to hospital is indicated in cases of erythroderma, and management is supportive, with intravenous fluids, warming measures, and treatment of infection. Topical corticosteroids are often prescribed but must be used with caution since significant amounts will be systemically absorbed across the erythrodermic skin. During recovery, the patient will desquamate, referred to as the exfoliative phase. Drugs commonly provoking this pattern of reaction are similar to those which cause a drug-induced exanthem (Box 56.12).

Lupus erythematosus

Syndromes indistinguishable from Lupus erythematosus (LE) may occur following drug administration (see Box 56.13) and can be accompanied by seroconversion to antinuclear antibody (ANA) positivity. Serological clearance of ANA may occur after drug withdrawal, but this may take months or years.

The cutaneous manifestations of drug-induced LE include the characteristic butterfly-shaped rash on the face, photosensitive erythema on dorsal hands and neck, and annular lesions on limbs.

Biological therapy targeting tumour necrosis factor alpha (TNF-α) such as infliximab and etanercept has been found to provoke lupus both in its systemic and limited cutaneous forms.

Vasculitis

Vasculitis is characterised pathologically by inflammation in vessel walls and clinically as palpable purpuric lesions most commonly found on the lower limbs. Cutaneous vasculitis without other organ involvement is the rule, but systemic involvement, such as renal, can occasionally occur. The purpuric areas on the legs may become ulcerated and require specialist dermatology input.

Drugs are the cause of approximately 10% of cutaneous vasculitis cases and should be considered in any patient with small vessel vasculitis (Box 56.14). Withdrawal of the causative drug is often sufficient to resolve the clinical manifestations without the need for treatment with systemic corticosteroids or more powerful immunosuppressants.

Skin necrosis

The term widespread cutaneous necrosis describes extensive skin infarction which often heralds a severe systemic coagulopathy. Widespread cutaneous necrosis can be triggered by a reaction to warfarin, or less commonly to heparin. In warfarin or coumarin skin necrosis, the buttocks and breasts are the most commonly involved sites. Discontinuation of the anticoagulant responsible is essential; however, ongoing management of the coagulopathy is critical and patients need to be assessed by a haematologist.

Patient care

Withdrawal of the likely offending drug should be the first intervention in cases of suspected drug eruption. This should be done in consultation with the prescribing physician, as an alternative drug may be required to control the patient’s condition. General methods which will provide symptomatic relief in a mild, limited drug eruption include emollients, soap substitutes and oral antihistamines. A mild topical corticosteroid may also be appropriate. In cases where the eruption is more extensive, or if a mucosal surface is involved, specialist care provided by a dermatologist will be necessary.

Case studies

Case 56.1

A 36-year-old female patient with a long history of chronic idiopathic urticaria attends her local pharmacy for some advice. Her skin disease is usually well controlled with an occasional dose of cetirizine which she buys over the counter. She has recently begun taking ibuprofen for muscular pain associated with her marathon training, but has found to her dismay that her urticaria has become much worse and is flaring on a daily basis.

Questions

1. What is the likely cause of the deterioration in the control of urticaria?

2. What management should be advised?

3. What other group of drugs is likely to produce this effect?

Answers

1. Non-steroidal anti-inflammatory drugs (NSAIDs) are known to increase the frequency of attacks of urticaria in susceptible individuals. It is likely that the self-medicating with ibuprofen has lessened the patient’s control of her urticaria.

2. In the first instance, the ibuprofen should be stopped. An alternative such as paracetamol could be advised for the musculoskeletal symptoms. An enquiry should be made as to whether or not any symptoms suggestive of angioedema, such as lip/tongue swelling, or difficulty breathing, have accompanied the urticaria, as this would imply a need for medical attention. In the acute phase, regular administration of an antihistamine such as chlorphenamine should help to relieve rapidly the symptoms. The patient should be warned that the ability of NSAIDs to worsen urticaria is a ‘class effect’ and that similar symptoms may be produced with drugs such as aspirin, meloxicam and naproxen.

3. Opiate analgesics lower the threshold for mast cell degranulation, which is the most important pathophysiological mechanism in the production of urticaria. Thus, morphine and related products such as codeine should be avoided.

Case 56.2

A 69-year-old male patient with a history of psoriasis attends the pharmacy looking for advice. In the past, his skin disease has always been well controlled with topical preparations. He was recently admitted to hospital with a myocardial infarction and has noticed a marked deterioration in his psoriasis since discharge. During his admission, he was commenced on:

Aspirin 75 mg daily

Simvastatin 20 mg daily

Atenolol 25 mg daily

Enalapril 5 mg daily

Questions

1. What is the likely reason for the exacerbation of his psoriasis?

2. How should this be treated?

Answers

1. The patient’s psoriasis could have worsened due to the stress of his recent illness, but it is probably secondary to the introduction of atenolol or enalapril. Both β-blockers and ACE inhibitors have been associated with the worsening of psoriasis.

2. Given the recent myocardial infarct, any interruptions or substitutions to treatment must be made in conjunction with the patient’s primary care doctor or cardiologist. The worsening of psoriasis with β-blockers is likely to be a class effect, and therefore substituting a different β-blocker is unlikely to resolve the problem. The treating physician may wish to prescribe an alternative antihypertensive such as a calcium channel blocker. If this does not ameliorate the situation, then the ACE inhibitor may be suspected, and trial stoppage may be considered. An ARB (angiotensin receptor blocker) such as candesartan may be acceptable as an alternative.

Case 56.3

A 37-year-old man presents with swelling of his upper lip. He asks if this could be stress induced as he has had several previous episodes of localised swelling of the face over the last 6–12 months.

He has been taking bendroflumethazide and enalapril for hypertension for the last 3 years, but has not taken any other medications recently.

Questions

1. What condition do his symptoms suggest?

2. Could this be drug-induced?

3. How should the condition be treated?

Answers

1. This pattern of localised swelling of the face is characteristic of angioedema.

2. Angioedema is a known adverse effect of ACE inhibitors with an overall incidence of 0.5–1%. Although this commonly occurs in the first week of treatment, delayed-onset angioedema can occur even after many years of treatment.

3. Since angioedema can be life-threatening, any suspect drug should be stopped. There is a very low incidence of this occurring with an angiotensin II receptor blocker (ARB), and this may be a suitable alternative for this patient. The acute presentation of angioedema is treated with antihistamine and corticosteroids. If the patient presents with respiratory symptoms, subcutaneous epinephrine (adrenaline) is indicated.

Case 56.4

Miss AF is a 15-year-old renal transplant patient who attends the pharmacy 6 weeks following transplant. She is very distressed about the growth of facial hair and the worsening of acne.

Questions

1. What are the possible causes of Miss AF’s skin complaints?

2. What other side effects should be enquired about?

3. How might these conditions be treated?

Answers

1. It is likely that Miss AF is receiving transplant immunosuppression that includes ciclosporin and prednisolone. The ciclosporin is most likely to have caused the growth of facial hair. Both the oral corticosteroid and the ciclosporin may have aggravated pre-existing acne or precipitated new-onset acne.

2. Ciclosporin may cause gingival hyperplasia, tremor, paraesthesia and nausea. Corticosteroids can cause increased appetite/weight gain, alterations of mood (euphoria, depression), sleep disturbance, gastritis and numerous other side effects.

3. Hirsutism is a side effect of ciclosporin that many young transplant patients have to cope with, and depilatory creams are commonly used. Tacrolimus is an alternative long-term immunosuppressant which is less likely to cause acne and hirsutism and which may be used in place of ciclosporin.

Case 56.5

An 85-year-old gentleman with rheumatoid arthritis, Mr DC, attends the local pharmacy with a persistent lesion on his left upper cheek, abutting the eyelid (Fig. 56.7), which has recently been bleeding. For the last 18 years, his rheumatoid arthritis has been treated with methotrexate. You know Mr DC is a retired naval officer, and his skin is severely sun damaged. He tells you he has had a number of basal cell carcinomas in the past and is concerned that this may be another.