Published: April 2012
An adverse drug reaction is any unintended or undesirable response to a medication given at an appropriate dose. Predictable adverse drug reactions, including toxicity, side effects, and drug interactions, are dose dependent and related to the pharmacologic actions of the drug. Unpredictable reactions, such as idiosyncratic and allergic reactions, are independent of dose and drug pharmacology.
Cutaneous reactions account for approximately 2% to 3% of all adverse drug reactions. Various patient- and drug-related factors contribute to the risk of adverse drug reactions. Patient factors include age (highest prevalence in the elderly); gender (more common in women); underlying disease (most prevalent in renal or hepatic disease, cystic fibrosis, and human immunodeficiency virus); and genetic differences in metabolizing enzymes. Drug factors include route of administration (more common with topical and intramuscular administration and less so with intravenous or oral administration); duration (more common with chronic or frequent use rather than short-term or intermittent use); dose; and variation in metabolism. Reactions are more common for drugs with low therapeutic indices, high levels of drug–drug interactions, and a tendency to form reactive intermediates or toxins. Even environmental factors can contribute to an adverse reaction. For example, ultraviolet light can alter the immunogenicity of certain medications, and viral infection, such as mononucleosis, can exacerbate the well-documented ampicillin-induced morbilliform reaction.
The mechanisms of drug-induced cutaneous reactions have not yet been clearly defined. Classically, there are four types of allergic reactions: type I, an immediate immunoglobulin E (IgE)-mediated hypersensitivity reaction; type II, a cytotoxic antibody reaction; type III, an immune-complex reaction; and type IV, a delayed hypersensitivity reaction, such as contact dermatitis.
However, most adverse drug reactions are not allergic and include toxicity, drug–drug interactions, and exacerbation of preexisting dermatologic diseases. Nonimmunologic activation of effector pathways, such as direct release of mast cell mediators and activation of complement without antibody formation, are also possible. Drugs also can alter arachidonic acid metabolism, explaining why aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can induce anaphylactic-type reactions without the formation of antibodies.
Drug reactions can be systemic or organ specific. Systemic reactions are anaphylaxis, vasculitis, serum sickness, and drug fever. Organ-specific reactions commonly affect the skin but can be hematologic, pulmonary, hepatic, or renal. The most common types of adverse cutaneous reactions are exanthems (46%), followed by urticaria (23%), fixed drug eruptions (10%), erythema multiforme (5.4%), and all other forms (less than 5%).
These can be maculopapular, morbilliform, or erythematous (Fig. 1). They are often bilateral and symmetrical in distribution and typically begin on the trunk or on pressure areas of bedridden patients. Mucosal involvement varies. Pruritus is usually present. Differentiating between drug-induced and infectious exanthems is often difficult. Drug-induced exanthems usually occur within a week of drug therapy, but they can occur as late as 2 weeks after therapy has ended. They often last 1 to 2 weeks and have a benign course. Any drug can cause an exanthem, but the most common agents are beta-lactam antibiotics, sulfonamides, erythromycin, gentamicin, anticonvulsants, and gold salts.
Urticaria and angioedema are less-common drug reactions, but they can progress to systemic anaphylaxis. Reaction can be immediate or delayed for days. Skin disease ranges from small papules to large annular (urticarial) plaques, often with pruritus. Individual lesions typically last less than 24 hours, but they can reappear. When the drug is discontinued, the lesions resolve rapidly. In angioedema, the mucous membranes are congested; when angioedema is severe, breathing and swallowing may be impaired. Allergic IgE-mediated urticaria and angioedema are often caused by antibiotics, especially penicillin, radiographic contrast media, and anesthetics. In contrast, angiotensin-converting enzyme inhibitors, NSAIDs, opiates, and curare can produce urticaria and angioedema that are not IgE mediated.
Vasculitis can affect the skin and other organs. Drug-induced cutaneous vasculitis typically begins as erythematous macules and papules on dependent areas (Fig. 2), which become tender and purpuric. Bullae and necrosis can occur. Affected patients often have fever, myalgias, arthralgias, and fatigue. Histologic changes include fibrinoid necrosis of small blood vessels and infiltration of leukocytes with disintegrating nuclei (leukocytoclastic vasculitis). Immunoglobulins within vessel walls suggest that vasculitis is an immune-complex disease, but the exact mechanism is unknown. Common culprits for drug-induced vasculitis include allopurinol, cimetidine, furosemide, penicillins, sulfonamides, hydantoins, and thiazide diuretics.
Fixed drug eruption is an uncommon occurrence characterized by a single or several erythematous, eczematous, or bullous plaques. Pruritus is rare, but burning and discomfort are possible. The face and genitalia are common sites of involvement. By definition, fixed drug reactions recur in the same location with repeated drug administration. The mechanism of action is unknown. Commonly implicated drugs are penicillins, tetracycline, sulfonamides, barbiturates, phenolphthalein, and gold salts. When the reaction resolves, it is often followed by hyperpigmentation.
Erythema multiforme is a hypersensitivity reaction characterized by macules, papules, and vesicles on the extremities and trunk, which often appear in a targetoid configuration (Fig. 3). Fever usually accompanies the reaction. The most common cause of erythema multiforme is infection, most often herpes simplex virus or mycoplasma, followed by drug sensitivity. Erythema multiforme can evolve to the more serious Stevens-Johnson syndrome, an extensive blistering disease involving two or more mucous membranes. The disease can be life threatening, with 5% mortality. Unlike erythema multiforme, Stevens-Johnson syndrome is usually drug induced. Signs and symptoms generally appear within 1 to 3 weeks of drug initiation. Incriminating drugs for both erythema multiforme and Stevens-Johnson syndrome include sulfonamides; aromatic anticonvulsants, such as phenobarbital, phenytoin, and carbamazepine; penicillins; quinolone; cephalosporins; NSAIDs; and allopurinol.
Toxic epidermal necrolysis is a severe life-threatening drug reaction that affects the skin and mucous membranes. It is characterized by confluent bullae and sheet-like epidermal shedding (Fig. 4). Fever and pain are common. Disease spreads quickly (within 2 to 3 days), and mortality can approach 30%. Infection is the leading cause of death. Affected patients experience impaired thermoregulation and electrolyte imbalance. Re-epithelialization occurs with scarring and pigmentation. Some patients have ocular sequelae, such as persistent dryness, photophobia, visual impairment, and even blindness. Histologically, epidermal necrosis occurs, whereas the dermis remains relatively unaffected. The etiologic agents for toxic epidermal necrolysis are the same as those for erythema multiforme and Stevens-Johnson syndrome.
Warfarin and heparin can induce skin necrosis. Warfarin necrosis occurs in 1 in 10,000 patients. It most commonly affects obese women who develop painful red plaques on the breasts, hips, and buttocks 3 to 5 days after therapy is initiated. Hemorrhagic bullae and necrosis follow and may require surgical débridement. Patients with protein C deficiency are at high risk for such skin necrosis because warfarin depresses this natural anticoagulant and induces a transient hypercoagulable state. Prompt recognition and treatment of warfarin necrosis can minimize fatalities.
Heparin necrosis is typically a localized reaction at injection sites and usually appears as purpuric plaques. Necrosis is triggered by thrombosis via platelet aggregation and the formation of fibrin thrombi. Thrombocytopenia is common, but fibrinogen and fibrin split products are normal. The reaction is probably immune mediated.
Systemic lupus erythematosus most commonly occurs with hydralazine and procainamide but can also occur with isoniazid, chlorpromazine, penicillamine, phenytoin, and sulfasalazine. The syndrome consists of constitutional symptoms (malaise, myalgias, arthralgias), fever, and erythematous plaques on the face. Affected patients have antinuclear antibodies that react only with histones; anti-DNA antibodies remain negative, and complement levels are normal. Other laboratory findings include elevated erythrocyte sedimentation rate, anemia, and leukopenia. Patients who have slow acetyltransferase activity are more likely to develop the syndrome.
Allergic contact dermatitis is the most common delayed-type hypersensitivity reaction. Skin disease follows topical application of an allergen and is characterized by erythematous, papular, urticarial, or vesicular plaques. Pruritus is common. If chronic, lichenification and thickening of the skin ensue. Sensitization occurs within 5 to 7 days, but the dermatitis recurs within 24 hours with reapplication of the allergen. Cross-reactivity with structurally related substances is possible. Any topical agent can induce contact dermatitis, but most common agents include topical antibiotics (neomycin, bacitracin), benzocaine, paraben, ethylenediamine, formaldehyde, para-aminobenzoic acid (PABA), and topical antihistamines. Although rare, allergic contact dermatitis can develop after application of topical corticosteroids and should be suspected if symptoms worsen during use of these preparations. Patch testing is a diagnostic tool used to identify the sensitizing agent.
Photosensitive dermatitis is the interaction between a drug and ultraviolet radiation. The reaction can be phototoxic or photoallergic. Disease begins after exposure to light, usually ultraviolet A (UVA) light. Phototoxic reactions resemble sunburn and are dose related. The drug probably absorbs and concentrates ultraviolet radiation in the skin. Phototoxicity can occur with use of coal tar derivatives, psoralen, chlorpromazine, tetracycline, and doxycycline. Reactions resolve when either ultraviolet radiation or the drug is discontinued. Photoallergic reactions are rare and vary from erythematous and eczematous plaques to bullae on sun-exposed skin. They appear within 1 to 3 weeks of treatment with a drug such as promethazine, PABA, NSAIDs, sulfonamides, griseofulvin, or psoralen. The exact mechanism is unknown, but photodermatitis may be a form of delayed-type hypersensitivity. In contrast to phototoxic reactions, photoallergic reactions can persist after discontinuation of the medication.
Various drug mechanisms can induce pigmentary changes in the skin. Some drugs, such as oral contraceptives, stimulate melanocytic activity. Others, including phenothiazines and heavy metals such as silver, mercury, and gold, become lodged within the skin and alter pigmentation directly. Antimalarials produce a slate gray or yellow pigmentation, and clofazimine produces a characteristic red color. Tetracycline can permanently stain teeth if taken during early childhood or pregnancy. Minocycline can produce a blue discoloration on mucosa, within scars, and on the shins. Amiodarone produces a characteristic slate blue discoloration in sun-exposed areas.
Accurate diagnosis of drug eruptions can be challenging. Clinical evaluation should include history and physical examination, with an attempt to distinguish drug eruptions from viral exanthem or preexisting skin disease. Sequence of events can help to differentiate the type of reaction. For example, urticaria and angioedema occur immediately after drug exposure in contrast to most other reactions. Any new dermatitis in a patient without prior skin disease should prompt consideration of drug sensitivity. The diagnosis can be straightforward when a patient who takes few or no medications develops a rash after starting a new drug. The challenge arises when a patient takes many medications, including a few new ones, any one of which can cause an adverse reaction.
To evaluate a patient’s drug sensitivity, the clinician needs to be aware of a drug’s potential to produce an adverse reaction, especially a drug’s dosing frequency and morphology of reactions. Evaluation should begin with a drug history, including identification of all drugs the patient has taken in the recent past. The clinician also needs to understand that adverse reactions can occur as late as 2 weeks after a medication has been discontinued. Knowledge of prior allergies helps to identify any cross-reactivity to current medications. For example, a patient with a penicillin allergy may develop an adverse reaction to other beta-lactam antibiotics. Once the suspected drug (or drugs) has been identified, discontinuation of the drug is warranted. If possible, all suspected drugs should be discontinued.
Several diagnostic tests can help to identify a suspected drug allergy; however, most have limited usefulness because many allergic reactions result from drug metabolites, which cannot be detected. Nonspecific hypersensitivity tests include a blood eosinophil count and measurement of the IgE level. For immediate-type reactions, determining the tryptase level may be helpful, because tryptase is a marker of mast cell degranulation. Immediate-type IgE reactions can be identified through skin testing; however, only a few drugs can be tested this way, with the most common being penicillin, cephalosporin, and latex. Assays to detect drug-specific IgG and IgM antibodies are also available. If medication toxicity is suspected, drug levels are essential.
Skin biopsy can be helpful for identifying a drug eruption. The presence of eosinophils, edema, and inflammation all suggest hypersensitivity. Vasculitis and necrotic changes may suggest erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis.
Patch testing is an important tool to evaluate the possibility of allergic contact dermatitis. As a test for reactivity, the application of specific allergens to the patient’s skin for 48 to 72 hours may identify an allergen to be avoided. Photopatch testing helps to evaluate photoallergic reactions. The approach is similar to standard patch testing except that the patient is exposed to both the drug and ultraviolet light.
Perhaps the most sensitive and specific diagnostic test for drug eruptions is the rechallenge. Whereas allergic drug reactions by definition should recur, nonallergic reactions may not. In fact, with some adjustments, such as elimination of drug-drug interactions or changing the dose to accommodate impaired metabolism, many drugs can be safely readministered. Drugs suspected to have caused severe reactions should never be taken again.
Treatment of drug eruptions is generally supportive. Symptomatic treatment primarily is predicated on the discontinuation of the offending agent, if possible. Antihistamines help to relieve pruritus and symptoms of urticaria and angioedema. Topical and systemic corticosteroids can provide additional relief. Topical corticosteroids are most beneficial for eczematous disease, but they provide little benefit in urticaria. Life-threatening reactions such as angioedema and anaphylaxis require prompt treatment with epinephrine, antihistamines, and/or systemic corticosteroids. The treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis includes fluid replacement, pain control, and often antibiotics to prevent secondary infection. The role of systemic corticosteroids, intravenous immunoglobulin, and plasmapheresis in these conditions is controversial. With parenteral vitamin K therapy, warfarin necrosis can be reversed, and systemic anticoagulation can be resumed using heparin. Treatment with monoclonal protein C concentrate is also helpful. Because the mechanisms of heparin and warfarin-induced necrosis are different, treatment with antiplatelet agents or warfarin can be helpful in heparin-induced necrosis.
If a patient requires a medication that previously produced a non–life-threatening drug reaction, premedicating each dose with systemic corticosteroids and antihistamines can significantly reduce the severity of the reaction. This approach is often used for patients who receive radiocontrast media. Desensitization can be considered for patients with an allergy to penicillins, cephalosporins, or sulfonamides.
Most drug eruptions are benign, but a small percentage can be extremely dangerous, including angioedema, vasculitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and anticoagulant necrosis. Therefore, prompt diagnosis and treatment—as well as future avoidance of the medication—are essential to reduce morbidity and mortality. If a medication is necessary, careful monitoring for severe reactions is important. The main caveat is that any medication has the potential to produce an adverse reaction, and any reaction has the potential to be life threatening.