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Adverse drug reactions are broadly defined by the World Health Organization as “any noxious, unintended, and undesired effect of a drug that occurs at doses used for prevention, diagnosis, or treatment.”1 These reactions can be classified into types A and B.

Type A reactions, which account for most adverse drug reactions, are predictable, dose dependent, and related to the pharmacologic mechanism of the drug. Examples include respiratory depression with the administration of increasing amounts of opiates or cushingoid features with chronic systemic steroid use. Type B reactions are unpredictable, dose independent, and not related to the drug’s pharmacologic actions. Allergic reactions to a medication are included in this type. Another example of a type B reaction is drug-induced lupus from minocycline.

Allergic reactions require prior sensitization and typically show signs consistent with an underlying allergic mechanism. They eventually resolve after the implicated drug is discontinued.2 Nonimmune hypersensitivity reactions, also termed pseudoallergic reactions, are clinically similar to allergic reactions but cannot be proved to be immunologic owing to a lack of detectable drug-specific antibodies or drug-specific T lymphocytes. Many causes for these reactions have been proposed, and they are dependent on the implicated drug. For example, the “allergic reaction” caused by radiocontrast material could be from nonspecific histamine release and complement activation, while the chronic cough seen with angiotensin-converting enzyme inhibitors could be from the accumulation of bradykinin.3 This chapter focuses primarily on immune-mediated type B reactions.


The immune-mediated reactions are organized according to the Gell and Coombs classification1 as follows:

  • Type I: immediate hypersensitivity reactions (anaphylaxis)

  • Type II: cytotoxic antibody reactions

  • Type III: immune complex reactions

  • Type IV: delayed hypersensitivity reactions

Type I reactions develop when a drug or drug metabolite interacts with preformed specific immunoglobulin E (IgE) antibodies bound to mast cells and basophils. This results in cross-linking of IgE FcεRl receptors on mast cells and basophils, leading to cellular degranulation and the release of histamine and leukotrienes. These released chemicals propagate urticaria, bronchospasm, vasodilation, and other manifestations of anaphylaxis (see Chapter 47). Type II reactions involve binding of IgG or IgM antibodies to recognized cell membrane–bound drug antigen. The cells become coated with antibody and are then injured via the complement system. Drug-induced hemolytic anemia is an example of such a reaction. Type III reactions are due to soluble antigen–antibody complexes deposited in the walls of blood vessels, which then activate the complement cascade. This is seen in serum sickness, which consists of fever, urticaria, lymphadenopathy, arthralgias, and a characteristic serpiginous rash at the interfacing dorsal-ventral regions of the hands and feet. Type IV reactions involve antigen-specific T-lymphocyte–mediated reactions, such as those seen in allergic contact dermatitis. Classifying drug hypersensitivities into one of these four categories may not always be possible.

A hapten is a small antigenic determinant that can cause ...

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