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.