Drugs can cause multiple skin eruptions and reactions. The most serious of these are discussed elsewhere in The Manual and include Stevens-Johnson syndrome and toxic epidermal necrolysis, hypersensitivity syndrome, serum sickness, exfoliative dermatitis, angioedema and anaphylaxis, and drug-induced vasculitis. Drugs can also be implicated in hair loss, lichen planus, erythema nodosum, pigmentation changes, SLE, photosensitivity reactions, pemphigus, and pemphigoid. Other drug reactions are classified by lesion type (see Table 1: Hypersensitivity and Inflammatory Disorders: Types of Drug Reactions and Typical Causative Agents).

Symptoms and Signs

Symptoms and signs vary based on the cause and the specific reaction (see Table 1: Hypersensitivity and Inflammatory Disorders: Types of Drug Reactions and Typical Causative Agents).

Table 1
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Types of Drug Reactions and Typical Causative Agents Type of Reaction Description and Comments Typical Causative Agents Acneiform eruptions Resemble acne but lack comedones and usually begin suddenly Corticosteroids, iodides, bromides, hydantoins, androgenic steroids, lithium, isoniazid, phenytoin, phenobarbital, vitamins B2, B6, and B12 Acral cyanosis Appears as gray-blue discoloration of tips of the fingers, toes, nose, and ears Bleomycin Blistering eruptions Appear with widespread vesicles and bullae resembling autoimmune bullous disorders (see Bullous Diseases) Penicillamine and other thiol-containing drugs (eg, ACE inhibitors, gold, Na thiomalate) Cutaneous necrosis Appears as demarcated, painful, erythematous or hemorrhagic lesions progressing to hemorrhagic bullae and full-thickness skin necrosis with eschar formation Warfarin, heparin, barbiturates, epinephrine, norepinephrine, vasopressin Drug-induced lupus Appears as lupus-like syndrome, although often without the rash Hydrochlorothiazide, minocycline, hydralazine, procainamide Erythema nodosum Characterized by tender red nodules, predominantly in the pretibial region, but occasionally involving the arms or other areas Sulfonamides, oral contraceptives Exfoliative dermatitis Characterized by redness, scaling, and thickening of the entire skin surface (see Dermatitis: Exfoliative Dermatitis) May be fatal Penicillin, sulfonamides, hydantoins Fixed drug eruptions Appear as frequently isolated, well-circumscribed, circinate or ovoid dusky red or purple lesions on the skin or mucous membranes (especially of the genitals) and reappear at the same sites each time the drug is taken Phenolphthalein, tetracycline, sulfonamides Lichenoid or lichen planus–like eruptions Appear as angular papules that coalesce into scaly patches (see Psoriasis and Scaling Diseases: Lichen Planus) Antimalarials, gold, chlorpromazine, thiazides Morbilliform or maculopapular eruptions (exanthems) Range in appearance from a morbilliform disease to an eruption resembling pityriasis rosea Mildly pruritic, typically appearing 3 to 7 days after start of the drug Almost any drug (especially barbiturates, analgesics, sulfonamides, ampicillin, and other antibiotics) Mucocutaneous eruptions Vary from a few small oral vesicles or urticaria–like skin lesions to painful oral ulcers with widespread bullous skin lesions (see Hypersensitivity and Inflammatory Disorders: Erythema Multiforme; see Hypersensitivity and Inflammatory Disorders: Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)) Penicillin, barbiturates, sulfonamides (including derivatives used to treat hypertension and diabetes) Photosensitivity eruptions Appear as areas of dermatitis or gray-blue hyperpigmentation (phenothiazines and minocycline) on skin exposed to the sun or other ultraviolet light source Phenothiazines, tetracyclines, sulfonamides, chlorothiazide, artificial sweeteners Purpuric eruptions Appear as nonblanching hemorrhagic macules that vary in size Most common on the lower extremities but may occur anywhere and may indicate a more serious purpuric vasculitis May occur as type II cytotoxic reactions, type IV cell-mediated delayed-type allergic reactions, or type III humoral allergic immune complex vasculitis Chlorothiazide, meprobamate, anticoagulants Serum sickness–type drug reaction A type III immune complex reaction Acute urticaria and angioedema more common than morbilliform or scarlatiniform eruptions Possibly polyarthritis, myalgias, polysynovitis, fever, and neuritis Penicillin, insulin, foreign proteins Stevens-Johnson syndrome Characterized by focal areas of skin necrosis and involvement of mucosa (see Hypersensitivity and Inflammatory Disorders: Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)) Lips develop hemorrhagic crusts and ulcerations Overlaps with toxic epidermal necrolysis Anticonvulsants, NSAIDs, penicillin, sulfonamides Toxic epidermal necrolysis Characterized by large areas of loosened, easily detached epidermis that give the skin a scalded appearance (see Hypersensitivity and Inflammatory Disorders: Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)) May be fatal in 30 to 40% of patients Resembles staphylococcal scalded skin syndrome (see Bacterial Skin Infections: Staphylococcal Scalded Skin Syndrome), a similar disorder that occurs in infants, young children, and immunosuppressed patients Overlaps with Stevens-Johnson syndrome Anticonvulsants, barbiturates, hydantoins, penicillin, sulfonamides Urticaria Common IgE-mediated Easily recognized by typical well-defined edematous wheals Occasionally the first sign of impending serum sickness, with fever, joint pain, and other systemic symptoms developing within days Penicillin, aspirin, sulfonamides Types of Drug Reactions and Typical Causative Agents Type of Reaction Description and Comments Typical Causative Agents Acneiform eruptions Resemble acne but lack comedones and usually begin suddenly Corticosteroids, iodides, bromides, hydantoins, androgenic steroids, lithium, isoniazid, phenytoin, phenobarbital, vitamins B2, B6, and B12 Acral cyanosis Appears as gray-blue discoloration of tips of the fingers, toes, nose, and ears Bleomycin Blistering eruptions Appear with widespread vesicles and bullae resembling autoimmune bullous disorders (see Bullous Diseases) Penicillamine and other thiol-containing drugs (eg, ACE inhibitors, gold, Na thiomalate) Cutaneous necrosis Appears as demarcated, painful, erythematous or hemorrhagic lesions progressing to hemorrhagic bullae and full-thickness skin necrosis with eschar formation Warfarin, heparin, barbiturates, epinephrine, norepinephrine, vasopressin Drug-induced lupus Appears as lupus-like syndrome, although often without the rash Hydrochlorothiazide, minocycline, hydralazine, procainamide Erythema nodosum Characterized by tender red nodules, predominantly in the pretibial region, but occasionally involving the arms or other areas Sulfonamides, oral contraceptives Exfoliative dermatitis Characterized by redness, scaling, and thickening of the entire skin surface (see Dermatitis: Exfoliative Dermatitis) May be fatal Penicillin, sulfonamides, hydantoins Fixed drug eruptions Appear as frequently isolated, well-circumscribed, circinate or ovoid dusky red or purple lesions on the skin or mucous membranes (especially of the genitals) and reappear at the same sites each time the drug is taken Phenolphthalein, tetracycline, sulfonamides Lichenoid or lichen planus–like eruptions Appear as angular papules that coalesce into scaly patches (see Psoriasis and Scaling Diseases: Lichen Planus) Antimalarials, gold, chlorpromazine, thiazides Morbilliform or maculopapular eruptions (exanthems) Range in appearance from a morbilliform disease to an eruption resembling pityriasis rosea Mildly pruritic, typically appearing 3 to 7 days after start of the drug Almost any drug (especially barbiturates, analgesics, sulfonamides, ampicillin, and other antibiotics) Mucocutaneous eruptions Vary from a few small oral vesicles or urticaria–like skin lesions to painful oral ulcers with widespread bullous skin lesions (see Hypersensitivity and Inflammatory Disorders: Erythema Multiforme; see Hypersensitivity and Inflammatory Disorders: Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)) Penicillin, barbiturates, sulfonamides (including derivatives used to treat hypertension and diabetes) Photosensitivity eruptions Appear as areas of dermatitis or gray-blue hyperpigmentation (phenothiazines and minocycline) on skin exposed to the sun or other ultraviolet light source Phenothiazines, tetracyclines, sulfonamides, chlorothiazide, artificial sweeteners Purpuric eruptions Appear as nonblanching hemorrhagic macules that vary in size Most common on the lower extremities but may occur anywhere and may indicate a more serious purpuric vasculitis May occur as type II cytotoxic reactions, type IV cell-mediated delayed-type allergic reactions, or type III humoral allergic immune complex vasculitis Chlorothiazide, meprobamate, anticoagulants Serum sickness–type drug reaction A type III immune complex reaction Acute urticaria and angioedema more common than morbilliform or scarlatiniform eruptions Possibly polyarthritis, myalgias, polysynovitis, fever, and neuritis Penicillin, insulin, foreign proteins Stevens-Johnson syndrome Characterized by focal areas of skin necrosis and involvement of mucosa (see Hypersensitivity and Inflammatory Disorders: Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)) Lips develop hemorrhagic crusts and ulcerations Overlaps with toxic epidermal necrolysis Anticonvulsants, NSAIDs, penicillin, sulfonamides Toxic epidermal necrolysis Characterized by large areas of loosened, easily detached epidermis that give the skin a scalded appearance (see Hypersensitivity and Inflammatory Disorders: Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)) May be fatal in 30 to 40% of patients Resembles staphylococcal scalded skin syndrome (see Bacterial Skin Infections: Staphylococcal Scalded Skin Syndrome), a similar disorder that occurs in infants, young children, and immunosuppressed patients Overlaps with Stevens-Johnson syndrome Anticonvulsants, barbiturates, hydantoins, penicillin, sulfonamides Urticaria Common IgE-mediated Easily recognized by typical well-defined edematous wheals Occasionally the first sign of impending serum sickness, with fever, joint pain, and other systemic symptoms developing within days Penicillin, aspirin, sulfonamides

Diagnosis

• Clinical evaluation and drug exposure history
• Sometimes skin biopsy

A detailed history is often required for diagnosis, including recent use of OTC drugs. Because the reaction may not occur until several days or even weeks after first exposure to the drug, it is important to consider all new drugs and not only the one that has been most recently started. No laboratory tests reliably aid diagnosis, although biopsy of affected skin is often suggestive. Sensitivity can be definitively established only by rechallenge with the drug, which may be hazardous and unethical in patients who have had severe reactions.

Treatment

• Discontinuation of offending drug
• Sometimes antihistamines and corticosteroids

Most drug reactions resolve when drugs are stopped and require no further therapy. Whenever possible, chemically unrelated compounds should be substituted for suspect drugs. If no substitute drug is available and if the reaction is a mild one, it might be necessary to continue the treatment under careful watch despite the reaction. Pruritus can be controlled with antihistamines and topical corticosteroids. For IgE-mediated reactions (eg, urticaria), desensitization (see Allergic, Autoimmune, and Other Hypersensitivity Disorders: Desensitization) can be considered when there is critical need for a drug.

When progression from urticaria to anaphylaxis is a concern, treatment is with aqueous epinephrine (1:1000) 0.2 mL sc or IM and with the slower-acting but more persistent soluble hydrocortisone 100 mg IV, which may be followed by an oral corticosteroid for a short period (see also Allergic, Autoimmune, and Other Hypersensitivity Disorders: Treatment).

Last full review/revision October 2009 by Wingfield E. Rehmus, MD, MPH