Chapter 056. Cutaneous Drug Reactions (Part 2)

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 animmunologic process. ...
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Chapter 056. Cutaneous Drug Reactions (Part 2) Chapter 056. Cutaneous Drug Reactions (Part 2) PATHOGENESIS OF DRUG REACTIONS Untoward cutaneous responses to drugs can arise as a result ofimmunologic or nonimmunologic mechanisms. A variety of adverse reactionsresult from mechanisms that do not involve an immunologic process. Drugreactions are a public health problem because of their frequent occurrence,occasional severity, and impact on the use of medications. The skin is among theorgans most often affected by adverse drug reactions. The list of conditions thatcan be triggered by medications includes nearly all dermatologic diseases. Manyof these adverse reactions result from mechanisms that do not involve animmunologic process. Obvious examples are pigmentary changes related toaccumulation in the dermis of amiodarone, antimalarials, minocycline, quinolones,alteration of hair follicules by cytostatics, and lipodystrophy associated withmetabolic effects of anti-HIV medications. These side effects are mostly toxic,predictable, and often can be avoided at least in part by simple preventivemeasures. Immunologic Drug Reactions For most acute drug eruptions, benign or severe, accumulated data suggestan immunologic basis. In the last 10 years drug-specific T cell clones were derivedfrom the blood lymphocytes or from skin lesions of patients with a variety of drugallergies. Since these clones had been obtained after several stimulations in vitrowith the drug, their relevance to explain the original manifestations of allergy canbe questioned. Regardless, these T cell clones brought definite evidence that drugscan be recognized as antigens by human T cells, and that these T cells play a rolein 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 CD4and CD8 clones were often obtained, whatever the clinical type of eruption. Some clones produced a TH0 profile of cytokines (simultaneous release ofIL-4 and IFN-γ). A TH2 orientation was frequent in CD4+ clones while CD8+clones were usually T H1 and often cytotoxic. Drug presentation to T cell wasMHC-restricted, usually as expected by HLA class II for CD4+ cells and by HLAclass I for CD8. But there were also less classic situations like HLA class IIrestricted cytotoxic CD4 clones. With many drugs, an original observation wasthat the drug could be presented to the TCR and activate a specific clone withoutprior processing by the antigen-presenting cell and through a noncovalent bindingto the MHC or its embedded peptide. Actually, some specific TCR couldrecognize sulfamethoxazole presented either in covalent or noncovalent boundform, but the former was the exception and the latter the rule. Since thenoncovalent binding is reminiscent of the pharmacologic interaction between adrug and its receptor, the denomination of pharmoco-immune (p-i) concept hasbeen proposed. Once a drug has induced an immune response, the final phenotype of thereaction probably depends on the nature of effectors: cytotoxic (CD8+) T cells inblistering reactions, chemokines for reactions mediated by neutrophils oreosinophils, and collaboration with B cells for production of specific antibodiesfor urticarial reactions. IMMEDIATE REACTIONS Immediate reactions depend on the release of mediators of inflammation bytissue mast cells or circulating basophilic leukocytes. These mediators includehistamine, leukotrienes, prostaglandins, platelet-activating factor, enzymes, andproteoglycans. Drugs can trigger mediator release either directly (anaphylactoidreaction) or through IgE-specific antibodies. These reactions are usually manifestin 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, anaphylacticshock with hypotension and death. They occur within minutes of drug exposure.Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, andradiocontrast media are frequent causes of pharmacologically mediatedanaphylactoid reactions, which can occur on first exposure. Penicillins andmyorelaxants used in general anesthesia are the most frequent causes of IgE-dependent reactions to drugs, which require prior sensitization. Release ofmediators is triggered when polyvalent drug protein conjugates cross-link IgEmolecules fixed to sensitized cells. Certain routes of administration favor differentclinical patterns (e.g., gastrointestinal effects from oral route, circulatory effectsfr ...