Adverse Reactions to Drugs

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Chapter 146 Adverse Reactions to Drugs

Adverse drug reactions can be divided into predictable (type A) and unpredictable reactions (type B). Predictable drug reactions, including drug toxicity, drug interactions, and adverse effects, are dose dependent, can be related to known pharmacologic actions of the drug, and occur in patients without any unique susceptibility. Unpredictable drug reactions are dose independent, often are not related to the pharmacologic actions of the drug, and occur in patients who are genetically predisposed. These include idiosyncratic reactions, allergic (hypersensitivity) reactions, and pseudoallergic reactions. Allergic reactions require prior sensitization, manifest as signs or symptoms characteristic of an underlying allergic mechanism such as anaphylaxis or urticaria, and occur in genetically susceptible individuals. They can occur at doses significantly below the therapeutic range. Pseudoallergic reactions resemble allergic reactions but are distinguished by the fact that an immunologic mechanism is not involved. Drug-independent cross-reactive antigens have been shown to induce sensitization manifesting as drug allergy. Patients with cetuximab-induced anaphylaxis were found to have immunoglobulin (Ig) E antibodies in pretreatment samples specific for galactose-α-l,3-galactose. The latter is present on the antigen-binding portion of the cetuximab heavy chain and is similar to structures in the ABO blood group.

Epidemiology

The incidence of adverse drug reactions in the general as well as pediatric populations remains unknown, although data from hospitalized patients show it to be 6.7%, with a 0.32% incidence of fatal adverse drug reactions. Databases such as the FDA MedWatch program (www.fda.gov/medwatch/index.html) likely suffer from underreporting. Cutaneous reactions are the most common form of adverse drug reactions, with ampicillin, amoxicillin, penicillin, and trimethoprim-sulfamethoxazole being the most commonly implicated drugs. Although the majority of adverse drug reactions do not appear to be allergic in nature, 6-10% can be attributed to an allergic or immunologic mechanism. Importantly, given the high probability of recurrence of allergic reactions, these reactions should be preventable, and information technology–based interventions may be especially useful to reduce risk of reexposure.

Pathogenesis and Clinical Manifestations

Immunologically mediated adverse drug reactions have been classified according to the Gell and Coombs classification: immediate hypersensitivity reactions (type I), cytotoxic antibody reactions (type II), immune complex reactions (type III), and delayed-type hypersensitivity reactions (type IV). Immediate hypersensitivity reactions occur when a drug or drug metabolite interacts with preformed drug-specific IgE antibodies that are bound to the surfaces of tissue mast cells and/or circulating basophils. The cross linking of adjacent receptor-bound IgE by antigen causes the release of preformed and newly synthesized mediators, such as histamine and leukotrienes, that contribute to the clinical development of urticaria, bronchospasm, or anaphylaxis. Cytotoxic reactions involve IgG or IgM antibodies that recognize drug antigen on cell membrane. In the presence of serum complement, the antibody-coated cell is either cleared by the monocyte-macrophage system or is destroyed. Examples are drug-induced hemolytic anemia and thrombocytopenia. Immune complex reactions are caused by soluble complexes of drug or metabolite in slight antigen excess with IgG or IgM antibodies. The immune complex is deposited in blood vessel walls and causes injury by activating the complement cascade, as seen in serum sickness. Clinical manifestations include fever, urticaria, rash, lymphadenopathy, and arthralgias. Symptoms typically appear 1-3 wk after the last dose of an offending drug and subside when the drug and/or its metabolite is cleared from the body. Delayed-type hypersensitivity reactions are mediated by drug-specific T lymphocytes. Sensitization usually occurs via the topical route of administration, resulting in allergic contact dermatitis. Commonly implicated drugs include neomycin and local anesthetics in topical formulations.

Certain adverse drug reactions, including drug fever and the morbilliform rash seen with use of ampicillin or amoxicillin in the setting of Epstein-Barr virus infection, are not easily classified. Studies now point to the role of T cells and eosinophils in delayed maculopapular reactions to a number of antibiotics. The mechanisms of T cell–mediated drug hypersensitivity are not well understood. A novel hypothesis suggests pharmacologic interactions of drugs with immune receptors. In T cell–mediated allergic drug reactions, the specificity of the T-cell receptor that is stimulated by the drug may be directed to a cross-reactive major histocompatibility complex–peptide compound. This information suggests that even poorly reactive native drugs are capable of transmitting a stimulatory signal via the T-cell receptor, which activates T cells and results in proliferation, cytokine production, and cytotoxicity. Previous contact with the causative drug is not obligatory, and an immune mechanism should be considered as the cause of hypersensitivity, even in reactions that occur with first exposure. Such reactions have been described for radiocontrast media and neuromuscular blocking agents.

Drug Metabolism and Adverse Reactions

Most drugs and their metabolites are not immunologically detectable until they have become covalently attached to a macromolecule. This multivalent hapten-protein complex forms a new immunogenic epitope that can elicit T- and B-lymphocyte responses. The penicillins and related β-lactam antibiotics are highly reactive with proteins and can directly haptenate protein carriers, possibly accounting for the frequency of immune-mediated hypersensitivity reactions with this class of antibiotics.

Incomplete or delayed metabolism of some drugs can give rise to toxic metabolites. Hydroxylamine, a reactive metabolite produced by cytochrome P450 oxidative metabolism, may mediate adverse reactions to sulfonamides. Patients who are slow acetylators appear to be at increased risk (Chapter 56). In addition, cutaneous reactions in patients with AIDS treated with trimethoprim-sulfamethoxazole, rifampin, or other drugs may be due to glutathione deficiency resulting in toxic metabolites. Serum sickness–like reactions in which immune complexes have not been documented, which occur most commonly with cefaclor, may result from an inherited propensity for hepatic biotransformation of drugs into toxic or immunogenic metabolites.

Risk Factors for Hypersensitivity Reactions

Risk factors for adverse drug reactions include prior exposure, previous reactions, age (20-49 yr), route of administration (parenteral or topical), dose (high), and dosing schedule (intermittent) as well as genetic predisposition (slow acetylators). Atopy does not appear to predispose patients to allergic reactions to low molecular weight compounds, but atopic patients in whom an allergic reaction develops have a significantly increased risk of serious reaction. Atopic patients also appear to be at greater risk for pseudoallergic reactions induced by radiocontrast media. Pharmacogenomics has an important role in identifying individuals at risk for certain drug reactions (Chapter 56).

Diagnosis

An accurate medical history is an important first step in evaluating a patient with a possible adverse drug reaction. Suspected drugs need to be identified along with dosages, route of administration, previous exposures, and dates of administration. In addition, underlying hepatic or renal disease may influence drug metabolism. A detailed description of past reactions may yield clues to the nature of the adverse drug reaction. The propensity for a particular drug to cause the suspected reaction can be checked with information in Physicians’ Desk Reference, Drug Eruption Reference Manual, or directly from the drug manufacturer. It is important to remember, however, that the history may be unreliable, and many patients are inappropriately labeled as being drug allergic. This label can result in inappropriate withholding of a needed drug or class of drugs. In addition, relying solely on the history can lead to overuse of drugs reserved for special indications, such as vancomycin in patients in whom penicillin allergy is suspected. Approximately 80% of patients with a history of penicillin allergy do not have evidence of penicillin-specific IgE antibodies on testing.

Skin testing is the most rapid and sensitive method of demonstrating the presence of IgE antibodies to a specific allergen. It can be performed with high molecular weight compounds such as foreign antisera, hormones, enzymes, and toxoids. Reliable skin testing can also be performed with penicillin but not with most other antibiotics. Most immunologically mediated adverse drug reactions are due to metabolites rather than to parent compounds, and the metabolites for most drugs other than penicillin have not been defined. In addition, many metabolites are unstable or must combine with larger proteins to be useful for diagnosis. Testing with nonstandardized reagents requires caution in interpretation of both positive and negative results, because some drugs can induce nonspecific irritant reactions. Whereas a wheal-and-flare reaction is suggestive of drug-specific IgE antibodies, a negative skin test result does not exclude the presence of such antibodies because the relevant immunogen may not have been used as the testing reagent.

A positive skin test response to the major or minor determinants of penicillin has a 60% positive predictive value for an immediate hypersensitivity reaction to penicillin. In patients in whom skin test responses to the major and minor determinants of penicillin are negative, 97-99% (depending on the reagents used) tolerate the drug without an immediate reaction. At present, the major determinant of penicillin testing reagent PrePen (penicyloyl-polylisne) in the USA is available, but the minor determinant mixture has not been approved by the U.S. Food and Drug Administration (FDA) as a testing reagent. The positive and negative predictive values of skin testing for antibiotics other than penicillin are not well established. Nevertheless, positive immediate hypersensitivity skin test responses to nonirritant concentrations of nonpenicillin antibiotics may be interpreted as a presumptive risk of an immediate reaction to such agents.

Results of direct and indirect Coombs tests are often positive in drug-induced hemolytic anemia. Assays for specific IgG and IgM have been shown to correlate with a drug reaction in immune cytopenia, but, in most other reactions, such assays are not diagnostic. In general, many more patients express humoral or T-cell immune responses to drug determinants than express clinical disease. Serum tryptase is elevated with systemic mast cell degranulation and can be seen with drug-associated mast cell activation, although it is not pathognomonic for drug hypersensitivity, and nonelevated tryptase values can be seen in well-defined anaphylaxis.

Treatment

Specific desensitization, which involves the progressive administration of an allergen to render effector cells less reactive, is reserved for patients with IgE antibodies to a particular drug for whom an alternative drug is not available or appropriate. Specific protocols for many different drugs have been developed. Desensitization should be performed in a hospital setting, usually in consultation with an allergist and with resuscitation equipment available at all times. Although mild complications, such as pruritus and rash, are fairly common and often respond to adjustments in the drug dose or dosing intervals and medications to relieve symptoms, more severe systemic reactions can occur. Oral desensitization may be less likely to induce anaphylaxis than parenteral administration. Pretreatment with antihistamines or corticosteroids is not usually recommended. It is important to recognize that desensitization to a drug is effective only while the drug continues to be administered and that after a period of interruption or discontinuation, hypersensitivity can recur.

Graded challenges based on the administration of a drug in an incremental fashion until a therapeutic dose is achieved can be attempted with drugs causing non–IgE-mediated reactions, including trimethoprim-sulfamethoxazole. Graded challenges in aspirin- or nonsteroidal anti-inflammatory drug (NSAID)–intolerant patients, particularly those with respiratory reactions, can also be performed. Gradual introduction of a drug may reveal systemic intolerance early enough to prevent progression to a serious or even life-threatening reaction such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).

β-Lactam Hypersensitivity

Penicillin is a frequent cause of anaphylaxis and is responsible for the majority of all drug-mediated anaphylactic deaths in the United States. Although IgE-mediated reactions may occur after administration of penicillin by any route, parenteral administration is more likely to cause anaphylaxis. If a patient requires penicillin and has a previous history suggestive of penicillin allergy, it is necessary perform skin tests on the patient for the presence of penicillin-specific IgE with both the major and minor determinants of penicillin. Skin tests for both major and minor determinants of penicillin are necessary because about 20% of patients with documented anaphylaxis do not demonstrate skin reactivity to the major determinant. Unfortunately, as mentioned earlier, the major determinant testing reagent, PrePen, was withdrawn from the market in the USA in 2004 owing to problems with manufacturing. The manufacturer, AllerQuest, LLC (West Hartford, CT), received approval from the FDA in January 2008 to manufacture Pre-Pen (www.allerquest.com/availability.html). The minor determinant mixture is currently not licensed and is synthesized as a nonstandardized testing reagent at select academic centers. Although penicillin G is often used as a substitute for the minor determinant mixture, there is a small but significant risk of false-negative skin test results with this approach. Thus, patients should be referred to an allergist capable of performing appropriate testing. If the skin test response is positive to either major or minor determinants of penicillin, the patient should receive an alternative non–cross reacting antibiotic. If administration of penicillin is deemed necessary, desensitization can be performed by an allergist in an appropriate medical setting. Skin testing for penicillin-specific IgE is not predictive for delayed-onset cutaneous, bullous, or immune complex reactions. In addition, penicillin skin testing does not appear to resensitize the patient.

Other β-lactam antibiotics, including semisynthetic penicillins, cephalosporins, carbacephems, and carbapenems, share the β-lactam ring structure. Patients with late-onset morbilliform rashes with amoxicillin are not considered to be at risk for IgE-mediated reactions to penicillin and do not require skin testing before penicillin administration. Up to 100% of patients with Epstein-Barr virus infections treated with ampicillin or amoxicillin can experience a nonpruritic rash. Similar reactions occur in patients who receive allopurinol as treatment for elevated uric acid or have chronic lymphocytic leukemia. If the rash to ampicillin or amoxicillin is urticarial or systemic or the history is unclear, the patient should undergo penicillin skin testing if a penicillin is needed. There have been reports of antibodies specific for semisynthetic penicillin side chains in the absence of β-lactam ring–specific antibodies, although the clinical significance of such side chain–specific antibodies is unclear.

Varying degrees of in vitro cross reactivity have been documented between cephalosporins and penicillins. Although the risk of allergic reactions to cephalosporins in patients with positive skin test responses to penicillin appears to be low (<2%), anaphylactic reactions have occurred after administration of cephalosporins in patients with a history of penicillin anaphylaxis. If a patient has a history of penicillin allergy and requires a cephalosporin, skin testing for major and minor determinants of penicillin should preferably be performed to determine whether the patient has penicillin-specific IgE antibodies. If skin test results are negative, the patient can receive a cephalosporin with no greater risk than found in the general population. If skin test results are positive for penicillin, recommendations may include: administration of an alternative antibiotic; cautious graded challenge with appropriate monitoring, with the recognition that there is a 2% chance of inducing an anaphylactic reaction; and desensitization to the required cephalosporin.

Conversely, patients who require penicillin and have a history of an IgE-mediated reaction to a cephalosporin should also undergo penicillin skin testing. Patients with a negative result can receive penicillin. Patients with a positive result should either receive an alternative medication or undergo desensitization to penicillin. In patients with a history of allergic reaction to one cephalosporin who require another cephalosporin, skin testing with the required cephalosporin can be performed, with the recognition that the negative predictive value of such testing is unknown. If the skin test response to the cephalosporin is positive, the significance of the test should be checked further in control subjects to determine whether the positive response is IgE mediated or an irritant response. The drug can then be administered by graded challenge or desensitization.

Carbapenems (imipenem, meropenem) represent another class of β-lactam antibiotics with a bicyclic nucleus that demonstrate a high degree of cross reactivity with penicillins, although prospective studies now suggest incidence of cross reactivity on skin testing of approximately 1%. In contrast to β-lactam antibiotics, monobactams (aztreonam) have a monocyclic ring structure. Aztreonam-specific antibodies have been shown to be predominantly side chain-specific; data suggest that aztreonam can be safely administered to most penicillin-allergic subjects. On the other hand, administration of aztreonam to a patient with ceftazidime allergy may be associated with increased risk of allergic reaction owing to similarity of side chains.

Sulfonamides

The most common type of reaction to sulfonamides is a maculopapular eruption often associated with fever that occurs after 7-12 days of therapy. Immediate reactions, including anaphylaxis as well as other immunologic reactions, have also been suggested. Hypersensitivity reactions to sulfonamides occur with much greater frequency in HIV-infected individuals. For patients in whom maculopapular rashes develop after sulfonamide administration, both graded challenge and desensitization protocols have been shown to be effective. These regimens should not be used in individuals with a history of SJS or TEN. Hypersensitivity reactions to sulfasalazine used for treatment of inflammatory bowel disease appear to result from the sulfapyridine moiety. Slow desensitization over ≈1 mo permits tolerance of the drug in many patients. In addition, oral and enema forms of 5-aminosalicylic acid (5-ASA), thought to be the pharmacologically active agent in sulfasalazine, are effective alternative therapies.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Blistering mucocutaneous disorders induced by drugs encompass a spectrum of reactions, including SJS and TEN (Chapter 646). Epidermal detachment of less than 10% is suggestive of SJS, 30% detachment suggests TEN, and 10-30% detachment suggests overlap of the two syndromes. The features of SJS include confluent purpuric macules on face and trunk and severe, explosive mucosal erosions, usually at more than one mucosal surface, accompanied by fever and constitutional symptoms. Ocular involvement may be particularly severe, and the liver, kidneys, and lungs may also be involved. TEN, which appears to be related to keratinocyte apoptosis, manifests as widespread areas of confluent erythema followed by epidermal necrosis and detachment with severe mucosal involvement. The risk of infection and mortality are high. Skin biopsy differentiates subepidermal cleavage characteristic of TEN from intraepidermal cleavage characteristic of the scalded-skin syndrome induced by staphylococcal toxins. TEN must be treated in a burn unit. Corticosteroids are contraindicated because they can significantly increase the risk of infection. High intravenous doses of immunoglobulin have been shown to be beneficial in patients with TEN, likely because of inhibition of Fas-mediated keratinocyte cell death by naturally occurring Fas-blocking antibodies in the intravenous immunoglobulin preparation.

Hypersensitivity to Antiretroviral Agents

A growing number of adverse drug reactions have been observed with antiretroviral agents, including reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. Hypersensitivity to abacavir is a well-recognized, multiorgan, potentially life-threatening reaction that occurs in HIV-infected children. The reaction is independent of dose, with onset generally within 9-11 days of initiation of drug therapy. Rechallenge can be accompanied by significant hypotension and potential mortality (rate of 0.03%), and thus hypersensitivity to abacavir is an absolute contraindication for any subsequent use. Prophylaxis with prednisolone does not appear to prevent hypersensitivity reactions to abacavir. Importantly, genetic susceptibility appears to be conferred by the HLA-B*5701 allele, with a positive predictive value of >70% and a negative predictive value of 95-98%. Genetic screening would be cost-effective in white populations but not in African or Asian populations, in which HLA-B*5701 allele frequency is <1%.

Chemotherapeutic Agents

Hypersensitivity reactions to chemotherapeutic drugs have been described, including to monoclonal antibodies. Data now suggest that rapid desensitization to a variety of unrelated agents, including carboplatin, paclitaxel, and rituximab, can be safely achieved in a 12-step protocol. Of note, this approach appears to be successful in both IgE-mediated and non–IgE-mediated reactions.

Biologics

An increasing number of biologic agents has become available for the treatment of autoimmune, allergic, cardiovascular, infectious, and neoplastic diseases. Their use may be associated with a variety of adverse reactions, including hypersensitivity reactions. Given the occurrence of anaphylaxis, including cases with delayed onset and protracted progression in spontaneous postmarketing adverse event reports, the FDA issued a boxed warning regarding risk of anaphylaxis and need for patient monitoring with use of omalizumab (Chapter 138).

Vaccines

Measles-mumps-rubella (MMR) vaccine has been shown to be safe in egg-allergic patients (although rare reactions to gelatin or neomycin can occur). The ovalbumin content in influenza vaccine is variable, and skin testing with the specific vaccine lot is warranted in patients with egg allergy. Patients with positive skin test responses can usually tolerate the vaccine when administered in 1/10 the full dose, followed 15-20 minutes later by 9/10 of the dose and then an observation period of 30 minutes. Of note, some patients who tolerate cooked egg (denatured egg protein) may still react to the vaccine. In addition, the newly introduced live intranasal influenza vaccine is contraindicated in egg-allergic children.

Perioperative Agents

Anaphylactoid reactions occurring during general anesthesia may be caused by induction agents (thiopental) or muscle-relaxing agents (succinylcholine, pancuronium). Quaternary ammonium muscle relaxants (succinylcholine) can act as bivalent antigens in IgE-mediated reactions. Negative skin test results do not necessarily predict that a drug will be tolerated. Latex allergy should always be considered in the differential diagnosis of a perioperative reaction.

Local Anesthetics

Adverse drug reactions associated with local anesthetic agents are primarily toxic reactions resulting from rapid drug absorption, inadvertent intravenous injection, or overdose. Local anesthetics are classified as esters of benzoic acid (group I) or amides (group II). Group I includes benzocaine and procaine; group II includes lidocaine, bupivacaine, and mepivacaine. In suspected local anesthetic allergy, skin testing followed by a graded challenge can be performed or an anesthetic agent from a different group can be used.

Insulin

Insulin use has been associated with a spectrum of adverse drug reactions, including local and systemic IgE-mediated reactions, hemolytic anemia, serum sickness reactions, and delayed-type hypersensitivity. In general, human insulin is less allergenic than porcine insulin, which is less allergenic than bovine insulin, but for individual patients, porcine or bovine insulin may be the least allergenic. Patients treated with nonhuman insulin have had systemic reactions to recombinant human insulin even on the first exposure. More than 50% of patients who receive insulin develop antibodies against the insulin preparation, although there may not be any clinical manifestations. Local cutaneous reactions usually do not require treatment and resolve with continued insulin administration, possibly owing to IgG-blocking antibodies. More severe local reactions can be treated with antihistamines or by splitting the insulin dose between separate administration sites. Local reactions to the protamine component of neutral protamine Hagedorn (NPH) insulin may be avoided by switching to Lente insulin. Immediate-type reactions to insulin, including urticaria and anaphylactic shock, are unusual and almost always occur after re-institution of insulin therapy in sensitized patients. Insulin therapy should not be interrupted if a systemic reaction to insulin occurs and continued insulin therapy is essential. Skin testing may identify a less antigenic insulin preparation. The dose following a systemic reaction is usually reduced to one third, and successive doses are increased in 2-5 unit increments until the dose resulting in glucose control is attained. Insulin skin testing and desensitization are required if insulin treatment is subsequently interrupted for more than 24-48 hr. Immunologic resistance usually occurs when high titers of predominantly IgG antibodies to insulin develop. A rare form of insulin resistance caused by circulating antibodies to tissue insulin receptors is associated with acanthosis nigricans and lipodystrophy. Coexisting insulin allergy may be present in up to a third of patients with insulin resistance. Approximately half of affected patients benefit from substitution with a less reactive insulin preparation, based on skin testing.

Drug-induced Hypersensitivity Syndrome

Drug-induced hypersensitivity syndrome, also referred to as DRESS (drug rash with eosinophilia and systemic symptoms) syndrome, is a potentially life-threatening syndrome that has been described primarily with anticonvulsants (Table 146-1). It is characterized by fever, maculopapular rash, generalized lymphadenopathy, and potentially life-threatening damage of one or more organs, including visceral organ involvement that resolves with discontinuation of the anticonvulsant. Drug-induced hypersensitivity syndrome/DRESS has also been described with minocycline, sulfonamides, aspirin, chlorambucil, and dapsone. Reactions are treated with discontinuation of the offending agent, systemic steroids, and supportive care.

Table 146-1 SERIOUS DRUG ERUPTIONS