Immunology icon Immunology Notes

Some Topics

Drug Allergy

Allergic drug reactions have always been recognized in the medical literature and drug product monographs. The "allergy" involved involves a spectrum of immune responses. While type 1 allergic reactions do occur and are sometimes expressed as life-threatening anaphylaxis, the majority of drug reactions are delayed, do not involve IgE antibodies, and do not show on skin tests.

Drug allergy is a prototype of delayed hypersensitivity diseases and can be used as a model of the kind of problems one should also expect from the prodigious array of antigenic molecules in the air, water and food supply. Food and drug antigens may be haptens or may be complete antigens in themselves - peptides, proteins, lectins, or dextrins. Swallowed materials trigger pathogenic events at sites distant from the gastrointestinal tract, often in complex sequences.

Hypersensitivity reactions represent about one third of all adverse drug reactions. Adverse drug reactions affect 10-20% of hospitalized patients and more than 7% of the general population. Any drug can cause an allergic response. Any tissue in the body can be a target and severe system illness sometimes precedes evidence of target organ damage. Skin eruptions, especially rashes and hives, are the most obvious target organ manifestations. Severe reactions, including anaphylaxis, Stevens Johnson syndrome and epidermal necrolysis are also associated with significant morbidity and mortality. Destruction of blood cells is a common occurrence with drug reactions, especially loss of platelets and red blood cells.

Antibiotics are responsible for up to 70% of allergic reactions: estimated frequency of reactions was 12.3% for cefaclor, 8.5% for sulfonamides, 7.4% for penicillins and 2.6% for cephalosporins. Demoly reported symptom patterns in 210 patients with proven beta-lactam antibiotic allergy. Symptoms included urticaria in 36.7% of patients, anaphylaxis without shock (19.1%), anaphylactic shock (17.6%), skin rash (19.1%), respiratory symptoms (1.9%). Anaphylactic shock and anaphylaxis occurred mainly within the first hour after drug administration, whereas skin eruption were delayed by at least 24 hours. Hives occurred at any time. Immediate skin tests were most commonly positive in patients with anaphylaxis. They decided that beta-lactam hypersensitivity reactions can be divided into three groups: anaphylaxis and anaphylactic shock (immediate reaction); skin eruptions (late reaction); and hives which occur at any time.

The Prozac (fluoxetine) product monograph describes allergic reactions to the drug: "Allergic reactions: Of 5600 patients given fluoxetine approximately 4% developed a rash and or urticaria... Reported in association with these allergic reactions include rash, fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase reactions... two patients are known to have developed a serious cutaneous, systemic illness. One was considered to have a leukocytoclastic vasculitis, and the other severe desquamation that was considered to be a vasculitis or erythema multiforme. Other patients have had systemic manifestations suggestive of serum sickness... events possibly related to vasculitis, have developed in patients with a rash. Although these events are rare, they made be serious, involving the lung, kidney or liver. Death has been reported to occur in association with systemic events. Anaphylaxis events include bronchospasm, angioedema, and urticaria, alone and in combination. Pulmonary events, including inflammatory processes of varying histopathology and or fibrosis have been reported. These events have occurred with dyspnea as the only preceding symptom. Whether these events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known."

Prozac, like many other drugs and like chemicals found in the food supply is capable of causing delayed hypersensitivity reactions with a spectrum of manifestations in many body systems. Although the product monograph declares that mechanism are unknown, it is likely that Prozac acts as a hapten, an incomplete antigen, and when associated with serum proteins, triggers any of the four immune hypersensitivity mechanisms in any combination with mixed results. The symptom complexes described in the monograph clearly involve more that one mechanism - the anaphylactic responses are probably triggered by circulating immune complexes (type 3 with) complement activation.

Inflammation in target organs is cell-mediated, type IV responses. Intravenous administration of drugs is more often associated with circulating immune complexes and delayed hypersensitivity. Taxol (pacitaxel) is another example that induces hypersensitivity in 39% of patients who take the drug; so often, that routine premedication with three allergy blocking drugs is recommended in the product brochure, dexamethasone, diphenhydramine and cimetadine. Angioedema, urticaria, dyspnea, and hypotension are the four most common manifestations of hypersensitivity reactions with this drug.

If you substitute any one of thousands of chemicals in food for Prozac or Taxol or other drugs that cause allergic reactions, you get the idea of the spectrum of problems related to delayed patterns of food allergy. One reason that food antigens are seldom recognized as a source of disease is the complexity and variability of the food supply. Antigens in food are numerous and seldom are discretely presented. Food antigens are variable; they change with variations in agricultural practice, food spoilage, contamination, preparation, cooking, and events in the digestive tract.

If physicians assumed that idiopathic hypersensitivity diseases originate from antigens in air and the food supply, then they would join us in the search for simple and effective solutions for common diseases.