Chapter 056. Cutaneous Drug Reactions (Part 2) pps

Chapter 056. Cutaneous Drug Reactions (Part 2) PATHOGENESIS OF DRUG REACTIONS Untoward cutaneous responses to drugs can arise as a result of immunologic or nonimmunologic mechanisms. A variety of adverse reactions result from mechanisms that do not involve an immunologic process. Drug reactions are a public health problem because of their frequent occurrence, occasional severity, and impact on the use of medications. The skin is among the organs most often affected by adverse drug reactions. The list of conditions that can be triggered by medications includes nearly all dermatologic diseases. Many of these adverse reactions result from mechanisms that do not involve an immunologic process. Obvious examples are pigmentary changes related to accumulation in the dermis of amiodarone, antimalarials, minocycline, quinolones, alteration of hair follicules by cytostatics, and lipodystrophy associated with metabolic effects of anti-HIV medications. These side effects are mostly toxic, predictable, and often can be avoided at least in part by simple preventive measures. Immunologic Drug Reactions For most acute drug eruptions, benign or severe, accumulated data suggest an immunologic basis. In the last 10 years drug-specific T cell clones were derived from the blood lymphocytes or from skin lesions of patients with a variety of drug allergies. Since these clones had been obtained after several stimulations in vitro with the drug, their relevance to explain the original manifestations of allergy can be questioned. Regardless, these T cell clones brought definite evidence that drugs can be recognized as antigens by human T cells, and that these T cells play a role in drug allergy. Specific clones were obtained with penicillin G, amoxicillin, cephalosporins, sulfamethoxazole, phenobarbital, carbamazepine, lamotrigine, i.e., many of the medications that are frequently a cause of drug eruptions. Both CD4 and CD8 clones were often obtained, whatever the clinical type of eruption. Some clones produced a T H 0 profile of cytokines (simultaneous release of IL-4 and IFN-γ). A T H 2 orientation was frequent in CD4+ clones while CD8+ clones were usually T H 1 and often cytotoxic. Drug presentation to T cell was MHC-restricted, usually as expected by HLA class II for CD4+ cells and by HLA class I for CD8. But there were also less classic situations like HLA class II restricted cytotoxic CD4 clones. With many drugs, an original observation was that the drug could be presented to the TCR and activate a specific clone without prior processing by the antigen-presenting cell and through a noncovalent binding to the MHC or its embedded peptide. Actually, some specific TCR could recognize sulfamethoxazole presented either in covalent or noncovalent bound form, but the former was the exception and the latter the rule. Since the noncovalent binding is reminiscent of the pharmacologic interaction between a drug and its receptor, the denomination of pharmoco-immune (p-i) concept has been proposed. Once a drug has induced an immune response, the final phenotype of the reaction probably depends on the nature of effectors: cytotoxic (CD8+) T cells in blistering reactions, chemokines for reactions mediated by neutrophils or eosinophils, and collaboration with B cells for production of specific antibodies for urticarial reactions. IMMEDIATE REACTIONS Immediate reactions depend on the release of mediators of inflammation by tissue mast cells or circulating basophilic leukocytes. These mediators include histamine, leukotrienes, prostaglandins, platelet-activating factor, enzymes, and proteoglycans. Drugs can trigger mediator release either directly ("anaphylactoid" reaction) or through IgE-specific antibodies. These reactions are usually manifest in the skin and gastrointestinal, respiratory, and cardiovascular systems (Chap. 311). Primary symptoms and signs include pruritus, urticaria, nausea, vomiting, cramps, bronchospasm, and laryngeal edema—and, occasionally, anaphylactic shock with hypotension and death. They occur within minutes of drug exposure. Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, and radiocontrast media are frequent causes of pharmacologically mediated anaphylactoid reactions, which can occur on first exposure. Penicillins and myorelaxants used in general anesthesia are the most frequent causes of IgE- dependent reactions to drugs, which require prior sensitization. Release of mediators is triggered when polyvalent drug protein conjugates cross-link IgE molecules fixed to sensitized cells. Certain routes of administration favor different clinical patterns (e.g., gastrointestinal effects from oral route, circulatory effects from intravenous route). IMMUNE COMPLEX–DEPENDENT REACTIONS Because the use of nonhuman sera is now uncommon, this mechanism is rarely relevant to adverse reactions seen today. Serum sickness is produced by tissue deposition of circulating immune complexes with consumption of complement. It is characterized by fever, arthritis, nephritis, neuritis, edema, and an urticarial, papular, or purpuric rash (Chap. 319). It was first described following administration of foreign sera; it may now occur with monoclonal antibodies. In classic serum sickness, symptoms develop 6 days or more after exposure to a drug, the latent period representing the time needed to synthesize antibody. Cephalosporin administration in febrile children may be associated with a clinically similar "serum sickness–like" reaction. The real mechanism of this reaction is unknown but is unrelated to complement activation. Cutaneous or systemic vasculitis, a relatively rare cutaneous complication of drugs, may also be a result of immune complex deposition (Chap. 319). . Chapter 056. Cutaneous Drug Reactions (Part 2) PATHOGENESIS OF DRUG REACTIONS Untoward cutaneous responses to drugs can arise as a result of immunologic. preventive measures. Immunologic Drug Reactions For most acute drug eruptions, benign or severe, accumulated data suggest an immunologic basis. In the last 10 years drug- specific T cell clones were. blistering reactions, chemokines for reactions mediated by neutrophils or eosinophils, and collaboration with B cells for production of specific antibodies for urticarial reactions. IMMEDIATE REACTIONS