Allergic and nonallergic drug reactions.

Abstract: Allergic drug reactions may be difficult to distinguish from nonallergic reactions. In this article, we review a pragmatic approach to the management of adverse drug reactions on the basis of knowledge of the classification and patterns of these reactions. Algorithms for management of patients with a previous adverse drug reaction who require treatment for the same indication, and the approach to a patient who experiences a drug reaction while on multiple drugs, are presented.

Key Words: anaphylaxis, drug reaction, hypersensitivity syndrome

**********

Most adverse drug reactions (ADRs) are not truly allergic in nature. Immunoglobulin (Ig) E-mediated drug allergy accounts for only 6 to 10% of all ADRs. (1) The mechanisms causing most adverse drug reactions are unknown, and diagnostic tests to confirm the allergic nature of reactions are often unavailable. We have proposed a method for management of drug reactions, which we review here. Management of clinical reactions to drugs remain empiric for the most part. It requires an understanding of the types of adverse reactions to the drugs that may occur and the structural and immunologic properties of drugs. Adverse reactions may be classified by type of reaction or by the organ system involved.

Classification by Type of Drug Reaction

A predictable drug reaction is seen in otherwise normal patients and is caused by a pharmacologic action of the drug (Table 1). Predictable drug reactions make up at least 80% of ADRs. Overdosage, or toxicity, is an exaggerated but expected effect caused by giving a supratherapeutic dose of a drug. Side effects occur with usual doses and are caused by undesired but known pharmacologic effects of a drug. Secondary effects are indirect pharmacologic effects that may be caused by both the disease and the drug. Teratogenic effects cause developmental defects in the fetus. Drug interactions are unusual effects that occur with two or more drugs administered simultaneously.

Unpredictable drug reactions are less common and are related to immunologic responses (hypersensitivity reactions) or to genetic differences in susceptible patients. Drug intolerance may occur even at subtherapeutic drug doses. Idiosyncratic reactions are rare, uncharacteristic responses to a drug that are unrelated to the pharmacologic actions of a drug, and may resemble an immunologic reaction. Some individuals have a genetic variability of drug metabolism that results in idiosyncrasy (eg, acute hemolytic anemia with dapsone in glucose-6-phosphate dehydrogenase deficiency). Allergic reactions are IgE-mediated hypersensitivity reactions that require prior exposure to the same or a chemically related drug, develop rapidly after reexposure, and are unrelated to the pharmacologic actions of the drug. Only a small dose of the suspected drug is needed to cause an allergic reaction. Anaphylactoid (or pseudoallergic) reactions mimic allergic reactions but do not have an immunologic mechanism (Table 1).

Classification of ADRs by Organ System Patterns

Certain drugs produce predictable patterns of ADRs, often involving specific organ systems. The more frequently encountered patterns are multisystem, dermatologic, hepatic, and respiratory.

Multisystem Patterns

Allergic (IgE-mediated) and anaphylactoid reactions (involving mast cell degranulation by other mechanisms) are often multisystemic. Symptoms include itching, flushing, urticaria, angioedema, laryngeal obstruction, bronchospasm, and hypotension (Fig. 1). Anaphylactic reactions may occur in response to any foreign protein to which the patient has been previously exposed. [beta]-Lactam antibiotics are among the most common drugs causing allergic reactions, with a prevalence of approximately 2% per course of therapy. (2) Most drugs have been reported to cause anaphylaxis, and cross-reactivity among chemically similar drugs may occur. For instance, patients with allergy to sulfonamide antimicrobial agents may react to thiazide diuretics, oral hypoglycemic agents, or celecoxib. Ingestion of opiates may activate opiate receptors on dermal mast cells, causing allergic-like but non-IgE-mediated anaphylactoid reactions manifested as urticaria and hypotension. Anaphylactoid reactions caused by iodinated radiocontrast media may occur by activation of the complement system with subsequent mast cell degranulation via mast cell complement receptors, or by direct osmotic effects on mast cells. Vancomycin, dextran, and polymyxin B may also cause anaphylactoid reactions.

True anaphylaxis and anaphylactoid reactions to local anesthetics are rare or nonexistent. Most ADRs to these agents represent vasovagal syncope, a side effect from inadvertent systemic administration. IgE to neuromuscular blockers may occur, causing severe reactions. However, some neuromuscular blockers such as tubocurarine may cause direct release of histamine.

Erythema multiforme (EM) consists of maculopapular eruptions and erythematous target lesions with central clearing. The lesions occur mainly on the extremities, with little truncal involvement. There may be minor involvement of the oral mucosa. Infections are the primary cause of EM minor (especially herpes simplex virus and Mycoplasma), which tends to be a self-limited condition lasting 2 to 4 weeks. Drug-induced EM is more likely to progress to the more severe Stevens-Johnson syndrome (SJS).

SJS begins with a macular rash that progresses to bulla, mucous membrane ulcerations, conjunctivitis, and fever (Fig. 2). It overlaps with and may evolve into the syndrome of toxic epidermal necrolysis (TEN) associated with extensive skin sloughing and a scalded skin appearance. Penicillin, sulfonamides, and other drugs have been associated with SJS and TEN. IV [gamma]-globulin and cyclosporine have been used successfully in the treatment of SJS. (3) Drugs suspected of causing SJS and TEN should be strictly avoided by the patient in the future.

The hypersensitivity syndrome is an ADR occurring primarily to aromatic antiepileptic agents, sulfonamides, and allopurinol. It is associated with a morbilliform to purpuric rash with one or more systemic manifestations, which include fever, lymphadenopathy, hepatitis, nephritis, carditis, eosinophilia, and atypical lymphocytes in the peripheral blood. It usually begins 2 to 6 weeks into therapy.

Serum sickness is an immune complex reaction that presents with fever, lymphadenopathy, joint pain and swelling, and cutaneous lesions (maculopapular, urticarial, or vasculitic). It is usually self-limited, beginning 6 to 21 days after administration of heterologous sera (such as horse antisera). Serum sickness-like reactions occur to [beta]-lactam and other antibiotics, and may persist for up to several weeks.

Drug fever may occur with any drug. Occasionally, the fever is associated with a maculopapular or urticarial rash, and leukocytosis is common. The causative mechanism is unknown. The fever usually resolves within 72 to 96 hours after withdrawal of the offending drug. The diagnosis is usually by exclusion of other possible causes of fever.

Dermatologic Patterns

Urticaria and/or angioedema may occur with almost any drug. Angioedema may begin several months into therapy with angiotensin-converting enzyme (ACE) inhibitors. Drug-related morbilliform dermatitis associated with [beta]-lactam antibiotics is usually a self-limited condition but sometimes may progress to more serious reactions (Fig. 3).

Contact dermatitis may result from numerous drugs when applied topically. The sensitizer may be a preservative or other excipient rather than the active drug. Subsequent administration of the drug by another route may lead to a generalized eczematoid reaction. The fixed eruption is a nummular eczema recurring in the same area on reexposure to a drug, and is thought to be lymphocyte mediated. A photoallergic reaction is an eczematous rash presumably caused by ultraviolet-induced immunogenic alterations of drugs in the skin. Phototoxic reactions are nonimmunologic blistering reactions that result from absorption and transmission of light energy by a drug in the skin.

Hepatic Patterns

Many drugs are concentrated in the liver, and reactive metabolites form in the liver, thereby predisposing this organ to drug reactions. Hepatic reactions may imitate acute or chronic hepatobiliary disease. Cholestatic reactions cause jaundice without elevation of enzymes other than alkaline phosphate, and fever, rash, and eosinophilia may be present. Chronic cholestasis may result. Erythromycin estolate has been implicated in such reactions more often than other erythromycin salts, probably because it is better absorbed. Elevated hepatic enzyme levels are seen in hepatocellular reactions and may lead to fulminant hepatic failure. Mixed patterns of cholestatic and hepatocellular disease occur. Granulomas of the liver may cause some hepatic necrosis, as in quinidine-induced hepatitis. Discontinuation of the culprit drug does not always result in resolution of liver injury.

[FIGURE 1 OMITTED]

Respiratory Patterns

Asthmatic reactions to inhaled proteins are usually IgE mediated, but asthmatic reactions to inhaled or ingested sulfites generally occur by a nonimmunologic mechanism. Wheezing and rhinitis caused by aspirin and nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity is also not IgE mediated.

Cough is the predominant symptom in the syndrome of drug-induced pulmonary infiltrates with eosinophilia. Chronic cough may develop with ACE inhibitors, but not with angiotensin II receptor antagonists. Pulmonary edema may occur in opiate overdoses, with toxic doses of salicylates, and with hydrochlorothiazide (but not with other thiazide diuretics).

[FIGURE 2 OMITTED]

Risk Factors for Drug Reactions

A number of factors influence the development of drug reactions that may be related to the patient or to the drugs themselves. Atypical drug metabolism predisposes to idiosyncratic and immunologic drug reactions. Drug metabolism proceeds by alternate pathways in the slow acetylator phenotype. Toxic metabolites form haptens with tissue proteins and produce neoantigens, such as the formation of reactive hydroxylamines from sulfonamides. Slow acetylators are at increased risk of developing drug-induced lupus.

The incidence of ADRs increases with age, because of abnormalities in drug pharmacology that occur with advancing age. Psychotropic and cardiovascular agents are the more common causes of serious ADRs in the elderly, perhaps because of the narrow therapeutic-toxic window with these drugs. Abnormalities of drug distribution, metabolism, excretion, and cellular response to drugs are present in the elderly, but drug absorption is usually normal. (4) Age-related decreases in serum albumin cause increased serum levels of highly protein-bound drugs. Changes in total body weight and lean body mass affect the volume of distribution and drug half-life. First-pass drug metabolism (oxidation, reduction, and hydroxylation) decreases with age, whereas second-pass metabolism (biotransformation, acetylation, and glucuronidation) is less affected. Creatinine clearance is decreased in the elderly, which causes significantly increased serum drug concentrations.

[FIGURE 3 OMITTED]

Specific human leukocyte antigen haplotypes are linked to an increased risk of developing immunologic reactions to certain medications. Atopic patients (with asthma, allergic rhinitis, or atopic dermatitis) do not have an increased risk for drug allergy. (1) However, a familiar tendency for drug allergy has been reported. A multiple-drug allergy syndrome occurs in some patients who have IgE-mediated reactions to many drugs. Female patients have a higher incidence of drug allergy than male patients.

[FIGURE 4 OMITTED]

Cystic fibrosis (CF) patients have a higher incidence of adverse drug reactions. Immediate allergic reactions occur in 28 to 34% of CF patients receiving parenteral antibiotics. (5), (6) Penicillins, cephalosporins, and aminoglycosides cause the most frequent reactions. Although it is not clear whether the mechanism(s) leading to antibiotic allergy in CF patients are different from those in the general population, the fact that CF patients are exposed to many courses of antibiotic agents is very likely a contributing factor.

[beta]-Blockers, including those in eyedrops, may trigger bronchospasm in patients with underlying bronchial hyperreactivity. [beta]-Blockers may also increase the severity of anaphylactic reactions and decrease the responsiveness to epinephrine.

Cutaneous drug reactions occur in up to 20% of human immunodeficiency virus-infected patients. (7) Most common are morbilliform rashes, which are usually mild and resolve after discontinuation of the culprit drug. Trimethoprim-sulfamethoxazole frequently causes rash and/or hives, which is postulated to be from a deficiency of glutathione, which detoxifies hydroxylamines.

Drug-related risk factors include the dose, duration of therapy, frequency of exposure, route of administration, and factors relating to the molecular nature of the drug itself. A single does is less sensitizing than high-dose parenteral therapy. Frequent courses of a drug are more sensitizing than courses separated by several years. Topical application of the drug carries the greatest risk of sensitization, and oral administration carries the least. Large macromolecular drugs, such as insulin or horse antisera, have a greater likelihood of causing drug reactions than smaller molecules. Some drugs (ie, penicillin) bond well to tissue proteins, called haptenation, making them potent antigens.

[FIGURE 5 OMITTED]

Drugs that Commonly Cause Hypersensitivity Reactions

Penicillin

The most frequent drugs to cause allergy are the penicillins. Cutaneous reactions occur more commonly than severe anaphylaxis. Certain metabolites of penicillin form stable haptens, bound to tissue proteins. The vast majority of IgE to penicillin is directed at the [beta]-lactam ring. Thus, a patient allergic to one penicillin is very likely allergic to all penicillins. Rarely, the IgE is directed at a side chain; this has been reported with amoxicillin.

Subsequent treatment is best limited to nonpenicillin drugs in a penicillin-allergic patient. Carbapenems (imipenem) have a high degree of cross-reactivity with penicillin, but monobactams (aztreonam) are generally tolerated. (2)

If penicillin is deemed absolutely necessary for treatment in a penicillin-allergic patient, skin testing to the major and three minor determinants (penicillin G, penicilloate, and penicilloate) should be done. Only the major determinant is commercially available. The minor determinants must be prepared by individual practices, which does not always result in reliable antigens for testing. Many allergists are capable of performing penicillin skin testing. If the skin testing is negative, the risk of anaphylaxis on readministration of penicillin at that time is less than 1%.

When skin testing is not available, or penicillin is the only appropriate drug in a patient with a positive penicillin skin test, desensitization may be attempted. The patient/family should be informed of the risks involved in desensitization, including anaphylaxis and death. Desensitization should only be attempted in an intensive care setting. Most regimens begin with a very diluted concentration of drug, and the dose is doubled every 15 to 20 minutes, until a full therapeutic dose is reached. This usually takes several hours and is not always successful. (3) In penicillin-allergic patients, the ability to detect IgE by skin testing decreases by approximately 10% per year, with less than 20% of patients remaining skin test positive after 10 years.

Cephalosporins

Cephalosporin allergy occurs in 5 to 10% of penicillin-allergic individuals, as compared with 1.7% of penicillin skin test-negative individuals. (2), (8) First- and second-generation cephalosporins have the greatest cross-reactivity with penicillins, and cross-reactivity is much less in the third-generation agents. Severe anaphylactic reactions to cephalosporins are extremely rare, occurring in <0.02%.

Skin testing to cephalosporins is less reliable. There are no cephalosporin haptenic determinants available for skin testing (as there are for penicillin). Allergy to cephalosporins in patients who are not penicillin allergic is usually caused by IgE against the unique side chain structure, not the [beta]-lactam ring. Desensitization may be attempted in cephalosporin-allergic patients if no alternative drug is available.

Aspirin and NSAID Sensitivity

Aspirin and other NSAIDs inhibit prostaglandin synthetase, inducing an overproduction of leukotrienes. Wheezing, rhinorrhea, nasal congestion, and conjunctivitis occur 30 minutes to 3 hours after ingestion of these drugs in sensitized patients. Chronic nonallergic rhinitis, nasal polyps, sinusitis, and asthma develop over time. The incidence of aspirin/NSAID hypersensitivity is increased in adult asthma patients as compared with the general population. Acetaminophen may cause similar respiratory responses, but they tend to be milder and of shorter duration. Aspirin desensitization and subsequent daily aspirin therapy is helpful in some patients with steroid-dependent asthma, nasal polyps, and/or sinusitis. Otherwise, avoidance of these drugs is advised.

Aspirin and NSAIDs may also cause acute urticaria, angioedema, and/or anaphylactoid reactions in patients without asthma or nasal polyps. A specific IgE against these drugs has not been found. Cross-reactivity with another cyclooxygenase inhibitor rarely occurs. Oral challenge to the culprit drug should be avoided in these patients, because of the risk of severe anaphylactoid reactions.

Aspirin and/or NSAID ingestion may exacerbate urticaria or angioedema in 20 to 30% of patients with chronic preexisting urticaria or angioedema. Avoidance of aspirin and NSAIDs is advised to prevent acute exacerbations but does not affect the chronic symptoms. Cyclooxygenase-2 inhibitors are well tolerated in patients with aspirin and NSAID-induced hypersensitivity.

Radiocontrast Media

Anaphylactoid reactions of pruritus, urticaria, angioedema, bronchospasm, hypotension, or syncope occur in up to 3% of patients receiving conventional high-osmolality radiocontrast media (RCM) and 0.5% of patients receiving nonionic, lower osmolality contrast media. No evidence of IgE to RCM has been shown. Fatalities occur in approximately 1 in 75,000 infusions. (3) One-fifth to one-third of patients with a prior RCM reaction will react on reexposure to conventional RCM. Other risk factors for RCM reactions include severe coronary artery disease, unstable angina, atopy, asthma, advanced age, and female sex. Nausea, emesis, flushing, and urticaria are the most common reactions. Most patients respond to epinephrine and antihistamines, but patients taking [beta]-blockers or ACE inhibitors may have severe hypotension that is less responsive to therapy.

Patients at risk for RCM reactions should receive nonionic RCM and premedication with prednisone and diphenhydramine (see Yates and deShazo (3) for protocol), which reduces the risk for a subsequent reaction to 3 to 10%. Informed consent should be obtained before initiating the pretreatment protocol.

Treatment of Patients with a History of a Drug Reaction Who Require Drug Treatment for the Same Indication

A practical approach for the patient with a history of a previous drug reaction who requires subsequent treatment for the same indication is outlined in Figure 4. First, determine what type of ADR the patient experienced. If the patient had a predictable drug reaction such as a side effect, modify the dose or change the drug if possible. A more detailed history may reveal only a poorly characterized rash that occurred in early childhood, which is unlikely to recur. The physician should correct the patient's chart regarding drug allergy and educate the patient. If review of the history reveals that a serious reaction is highly unlikely but further security is desired, the consenting patient may be given a small test dose in a setting where anaphylaxis can be adequately treated.

Unpredictable drug reactions including intolerance, idiosyneratic reactions, serum sickness, drug fever, or bullous skin disorders (SJS and TEN) require avoidance of the responsible drug and others of the same chemical class in the future. If the reaction was allergic or pseudoallergic, treatment should be limited to structurally unrelated drugs in the future. If the same class of drug is absolutely required for therapy, skin testing (for IgE-mediated reactions to penicillin) and/or desensitization may be performed. Personnel familiar with and equipped to treat anaphylaxis must be available throughout the procedure, because anaphylaxis may result.

Drugs that have been used for skin testing in the native form include semisynthetic penicillins (up to 3 mg/ml), cephalosporins (up to 3 mg/ml), aminoglycosides (up to 1 mg/ml), imipenem (up to 1 mg/ml), and vancomycin (up to 0.1 mg/ml) (2) Negative skin tests to the native drug do not rule out the possibility of allergy to these drugs, because the antigen may only be present on a metabolic product of the drug. (9) In vitro tests may be substituted for skin tests in some cases but are generally regarded as being less reliable. Negative skin testing (when the histamine control is positive) is immediately followed by a challenge procedure. A positive skin test (in the presence of a negative saline control test) indicates that drug-specific IgE is present. Desensitization may be attempted if the skin test is positive. Drugs for which a positive skin test is often followed by desensitization include [beta]-lactam antibiotics and proteins, such as insulin.

Desensitization to a limited number of drugs has been successful even when skin testing is not available or is unreliable. Most regimens begin with a very dilute concentration of the drug, and the dose is doubled every 15 to 20 minutes, until a full therapeutic dose has been administered after 3 to 8 hours. Desensitization is usually maintained as long as the drug is administered, at least every 12 hours, but may have to be repeated if therapy is interrupted. Oral desensitization appears to be safer than parenteral desensitization when the drug is well absorbed orally. Desensitization for less acute immunologic reactions to drugs such as trimethoprim-sulfamethoxazole has been successfully performed over a period of several days to weeks. Desensitization to NSAIDs has been successful for asthmatic but not urticarial or anaphylactic reactions. Premedication with corticosteroid and antihistamine aids in minimizing or preventing anaphylactic reactions (such as to RCM) with readministration of the drug.

Treatment of Patients with Drug Reactions While Taking Multiple Drugs

Drug reactions that occur while a patient is taking multiple drugs may be more difficult to evaluate and manage. The most recently administered drug is often the culprit, but delayed-onset reactions such as serum sickness may occur to a drug previously administered. The clinical approach should be organized in such a way as to facilitate a resolution of the reaction while providing useful information as to the drug responsible for the reaction, if possible. One approach is outlined in Figure 5. The information provided in the preceding paragraphs and tables provides the basis for postulation of the most likely drug causing the reaction. For instance, the most likely drugs causing multisystem reactions are antibiotics, including antituberculosis and antifungal drugs, diuretics, anticonvulsants, allopurinol, coumarin, heparin, oral hypoglycemics, and antiarrhythmic agents. The ADR provides an opportunity to review the patient's therapy and eliminate nonessential drugs.

Key Points

* Most drug reactions are not allergic.

* Knowledge of the expected patterns of drug reactions usually allows the correct identification of the drug causing the adverse reaction.

* Patients with immunoglobulin E-mediated drug allergy may be desensitized to the drug if no alternative drug is available.

From the Departments of Pediatrics and Medicine, University of Mississippi Medical Center, Jackson, MS.

Reprint requests to Anne B. Yates, MD, Department of Pediatrics, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216. Email: [e-mail]

Accepted August 19, 2003.

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9611-1080

References

1. DeSwarte RD, Patterson R. Drug allergy, in Patterson R, Grammer LC, Greenberger PA (eds): Allergic Diseases: Diagnosis and Management. Philadelphia, Lippincott-Raven, 1997, ed 5, pp 317-412.

2. Shepherd GM. Allergy to [beta]-lactam antibiotics. Immunol Allergy Clin North Am 1991;11:611-633.

3. Yates AB, deShazo RD. Drug allergies and hypersensitivity, in Rich RR, Fleisher TA, Shearer WT, et al (eds): Clinical Immunology: Principles and Practice. St. Louis, Mosby, 2001, vol 1, ed 2, pp 54.1-54.13.

4. Hanlon JT, Shimp LA, Semla TP. Recent advances in geriatrics: Drug-related problems in the elderly. Ann Pharmacother 2000;34:360-365.

5. Wills R, Henry RL, Francis JL. Antibiotic hypersensitivity reactions in cystic fibrosis. J Paediatr Child Health 1998;34:325-329.

6. Pleasants RA, Walker TR, Samuelson WM. Allergic reactions to parenteral [beta]-lactam antibiotics in patients with cystic fibrosis. Chest 1994;106:1124-1128.

7. Heller HM. Adverse cutaneous drug reactions in patients with human immunodeficiency virus-1 infection. Clin Dermatol 2000;18:485-489.

8. Kelkar PS, Li JT. Cephalosporin allergy. N Engl J Med 2001;345:804-809.

9. Gruchalla R. Understanding drug allergies. J Allergy Clin Immunol 2000;105:S637-S644.

RELATED ARTICLE: Table 1. Classification of adverse drug reactions with some representative examples (a)

Predictable adverse reactions

Toxicity caused by overdosage: seizures secondary to theophylline

Side effects, immediate or delayed: sedation with antihistamines

Secondary or indirect effects

Related to drug alone: disturbance of bacterial flora

Related to both disease and drugs: maculopapular rash to ampicillin with viral infections

Interactions between or among drugs: bleeding with warfarin and cimetidine combination

Unpredictable reactions

Intolerance (a known effect occurring with an unusually small dose): tinnitus caused by small doses of aspirin

Idiosyncratic reactions in patients with abnormal metabolism

Reactions involving mast cell mediator release

Allergic reactions caused by IgE

Anaphylactoid reactions (mast cell mediator release without IgE involvement): opiates, radiocontrast media, deferoxamine, vancomycin, taxol

Probable accumulation of bradykinin: cough, angioedema from ACE inhibitors

Probable excess leukotriene production: aspirin-induced asthma and urticaria

Bronchospasm: inhaled or ingested sulfites, [beta]-blockers

(a) IgE, immunoglobulin E: ACE, angiotensin-converting enzyme. Adapted from. DeSwarte RD, Drug allergy, in Patterson R (ed): Allergic Diseases: Diagnosis and Management. Philadelphia, J.B. Lippincott, 1993, ed 4. (1)

RELATED ARTICLE: Table 2. Some organ-specific patterns of adverse drug reactions (a)

Multisystem patterns

Anaphylactic-anaphylactoid: antimicrobials, proteins, iodinated contrast media, NSAIDs, ethylene oxide, Taxol

Stevens-Johnson syndrome or toxic epidermal necrolysis: sulfonamides, [beta]-lactam antibiotics, hydantoins, carbamazepine 

Hypersensitivity syndrome: anticonvulsants, sulfonamides, allopurinol

Serum sickness or vasculitis: proteins, antimicrobials, allopurinol, thiazides, pyrazolones, hydantoins, propylthiouracil

Drug fever: bleomycin, amphotericin B, sulfonamides, [beta]-lactam antibiotics, methyldopa, quinidine, procainamide

Drug-induced lupus: hydralazine, procainamide, isoniazid, methyldopa, chlorpromazine, quinidine, anticonvulsants

Dermatologic patterns

Urticaria-angioedema: same as for anaphylactic reactions, plus opiates

Isolated angioedema: ACE inhibitors

Pruritus without urticaria: gold, sulfonamides

Morbilliform rashes: penicillins, sulfonamides, barbiturates, antituberculosis drugs, anticonvulsants, quinidine

Fixed eruption: phenolphthalein, analgesic-antipyretics, barbiturates, [beta]-lactam antibiotics, sulfonamides, tetracycline

Photoallergic photosensitivity: phenothiazines, sulfonamides, griseofulvin 

Phototoxic photosensitivity: tetracyclines, sulfanilamide, chlorpromazine, psoralens

Contact dermatitis: local anesthetics, neomycin, paraben esters, ethylenediamine, antihistamines, mercurials

Hepatic patterns

Cholestasis: macrolides, phenothiazines, hypoglycemics, imipramine, nitrofurantoin 

Hepatocellular: valproic acid, halothane, isoniazid, methyldopa, quinidine, nitrofurantoin, phenytoin, sulfonylureas

Granulomatous: quinidine, allopurinol, methyldopa, sulfonamides

Renal patterns

Nephrosis (membranous glomerulonephritis): gold, captopril, NSAIDs, penicillamine, probenecid, anticonvulsants

Acute interstitial nephritis: [beta]-lactams (especially methicillin), rifampin, NSAIDs, sulfonamides, captopril, allopurinol

Respiratory patterns

Rhinitis: reserpine, hydralazine, [alpha]-receptor blockers, anticholinesterases, iodides, levodopa, triethanolamine

Asthma: inhaled proteins (pancreatic extract, psyllium), [beta]-lactam antibiotics, sulfites, NSAIDs, [beta]-receptor blockers

Cough: ACE inhibitors

Pulmonary infiltrates with eosinophilia: nitrofurantoin, methotrexate, NSAIDs, sulfonamides, tetracycline, isoniazid

Chronic fibrotic reactions: nitrofurantoin, cytotoxic chemotherapeutics

Hematologic patterns

Eosinophilia: gold, allopurinol, 5-ASA, ampicillin, tricyclics, capreomycin, carbamazepine, digitalis, phenytoin

Thrombocytopenia: quinidine, sulfonamides, gold, heparin

Hemolytic anemia (Coombs' positive)

Hapten-carrier mechanism: penicillin, cisplatin

"Innocent bystander": sulfonamides, quinines, chlorpromazine, para-aminosalicylic acid

Drug-induced autoimmune antibodies: methyldopa, penicillin

Granulocytopenia: sulfasalazine, procainamide, penicillins, phenothiazines

Reticuloendothelial patterns

Lymphadenopathy: phenytoin, penicillin, aminosalicylic acid, dapsone

(a) NSAIDs, nonsteroidal anti-inflammatory drugs; 5-ASA, 5-acetylsalicylic acid; ACE, angiotensin-converting enzyme. Adapted from, DeSwarte RD. Drug allergy, Patterson R (ed): Allergic Diseases: Diagnosis and Management. Philadelphia, J.B. Lippincott, 1993, ed 4, p 395. (1)

Anne B. Yates, MD, and Richard D. deShazo, MD