Drug Eruptions and Reactions

By Wingfield E. Rehmus, MD, MPH, Clinical Assistant Professor, University of British Columbia

NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version

Hypersensitivity and Inflammatory Disorders
Introduction to Hypersensitivity and Inflammatory Disorders
Acute Febrile Neutrophilic Dermatosis
Drug Eruptions and Reactions
Erythema Multiforme
Panniculitis
Erythema Nodosum
Granuloma Annulare
Pyoderma Gangrenosum
Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

Drugs can cause multiple skin eruptions and reactions. The most serious of these are discussed elsewhere in TheManual 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 ( Types of Drug Reactions and Typical Causative Agents).

Symptoms and Signs

Symptoms and signs vary based on the cause and the specific reaction ( Types of Drug Reactions and Typical Causative Agents).

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
Acute generalized exanthematous pustulosis	Rapidly appearing and spreading pustular eruption	Aminopenicillins (ampicillin, amoxicillin, and bacampicillin), Ca channel blockers, cephalosporins, tetracyclines
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, levamisole (contaminant in street preparations of cocaine)
Drug-induced lupus	Appears as lupuslike syndrome, although often without the rash	Hydrochlorothiazide, minocycline, hydralazine, procainamide, anti-TNF agents
Drug reaction with eosinophilia and systemic symptoms or drug hypersensitivity syndrome	Manifests as fever, facial edema, and rash 2–6 wk after 1st dose of a drug Patients may have elevated eosinophils, atypical lymphocytes, hepatitis, pneumonitis, lymphadenopathy, and myocarditis	Anticonvulsants, allopurinol, sulfonamides
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 and scaling of the entire skin surface (see 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	Tetracyclines, sulfonamides, NSAIDs
Lichenoid or lichen planus–like eruptions	Appear as angular papules that coalesce into scaly plaques (see Lichen Planus)	Antimalarials, 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 Erythema Multiforme and see 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 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 Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)) May be fatal in 30 to 40% of patients Resembles staphylococcal scalded skin syndrome (see 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 Classically but not always 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, ACE inhibitors

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 and urticaria can be controlled with oral antihistamines and topical corticosteroids. For IgE-mediated reactions (eg, urticaria), desensitization (see Drug Hypersensitivity : Desensitization) can be considered when there is critical need for a drug.

If anaphylaxis occurs, treatment is with aqueous epinephrine (1:1000) 0.2 mL sc or IM, parenteral antihistamines, 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.

Key Points

Because drugs can cause a wide variety of reactions, drugs should be considered as causes of almost any unexplained skin reaction.
Base the diagnosis primarily on clinical criteria, including a detailed history of prescription and OTC drugs.
Stop the suspected offending drug and treat symptoms as needed.