View metadata, citation and similar papers at core.ac.uk brought to you by CORE Acta Dermatovenerol Croat 2009;17(1):54-69 REVIEW Nonallergic Hypersensitivity to Nonsteroidal Antiinflammatory Drugs, Angiotensin-Converting Enzyme Inhibitors, Radiocontrast Media, Local Anesthetics, Volume Substitutes and Medications used in General Anesthesia Ružica Jurakić Tončić, Branka Marinović, Jasna Lipozenčić University Department of Dermatology and Venereology, Zagreb University Hospital Center and School of Medicine, Zagreb, Croatia Corresponding author: SUMMARY Urticaria and angioedema are common allergic manifestations Professor Jasna Lipozenčić, MD, PhD and medications are one of common triggering factors. The most severe immediate drug reaction is anaphylaxis. Apart from the well established University Department of Dermatology IgE-mediated immediate type hypersensitivity reactions, the pathogenesis and Venereology of drug-induced urticaria, angioedema and anaphylaxis often remains ob- Zagreb University Hospital Center scure. In this article, emphasis is put on nonallergic reactions to the most commonly used drug groups of nonsteroidal antiinflammatory drugs, an- and School of Medicine giotensin-converting enzyme inhibitors, radiocontrast media, volume ex- Šalata 4 panders and drugs used in general anesthesia. Urticaria is the second HR-10000 Zagreb most common drug eruption after maculopapular exanthema. The mecha- nisms of acute urticarial reactions are multiple, mostly IgE mediated, but Croatia some drugs can induce immune complex reactions and activate comple- [email protected] ment cascade, while others can induce direct activation of mast cells and degranulation or activation of complement by non-immune mechanisms. Received: December 20, 2008 With different types of medications different pathomechanisms are in- volved. Non-steroid anti-inflammatory drugs are thought to cause reaction Accepted: February 20, 2009 due to cyclooxygenase-1 inhibition and overproduction of leukotrienes, blamed for cutaneous and respiratory symptoms. Angiotensin-converting enzyme inhibitors can cause fatal angioedema, which is partially explained with bradykinin excess and impairment of aminopeptidase P and dipepti- dyl peptidase IV that are involved in the metabolism of substance P and bradykinin. It remains unknown what additional mechanisms are involved. Radiocontrast media and local anesthetics mostly cause nonallergic hy- persensitivity reaction, but in rare cases true allergic reaction can occur. Dextran is known to cause IgG mediated, immune complex anaphylaxis and it is recommended to use human serum albumin as the safest colloid. KEY WORDS: pseudoallergy, nonallergic hypersensitivity, drug intoler- ance, drug hypersensitivity, anaphylactoid reaction, allergy-like reactions INTRODUCTION Specific intolerance reactions to medications described in 1901 by Hirschberg and was termed are not based on sensitization of the immune sys- „idiosyncrasy“. This term is today frequently used tem. For the first time, intolerance to aspirin was for similar reactions to local anesthetics, contrast 54 Jurakić Tončić et al. Acta Dermatovenerol Croat Nonallergic hypersensitivity to different drugs 2009;17(1):54-69 media, natural and artificial food ingredients. Sev- delivery of drugs (6). Nanoparticulate vehicle sys- eral terms have been used such as idiosyncrasy, tems are very useful but also imply a high risk of intolerance, pseudoallergy and nonallergic hy- acute hypersensitive reactions that are not IgE persensitivity. According to revised terminology mediated. These reactions are called nonallergic from 2003, The European Academy of Allergol- hypersensitivity, are distinguished from type I re- ogy and Clinical Immunology has suggested that action by Coombs and Gell and have been termed each condition should be categorized as allergic “complement activation-related pseudoallergy” or nonallergic, and terms that are no longer in use (CARPA) (Table 1). Medications that can cause are idiosyncrasy (now hypersensitivity), pseudoal- CARPA are radiocontrast media, some liposomal lergy (now nonallergic hypersensitivity), and ana- drugs (Doxil, Ambisome and DaunoXome) and mi- phylactoid reaction (now nonallergic anaphylaxis) cellar solvents containing amphiphilic lipids (Cre- (1,2). mophor EL, the vehicle of Taxol). These agents Pseudoallergy or nonallergic hypersensitivity is activate complement system through the classic a nonimmune hypersensitivity reaction that mim- and the alternative pathways, giving rise to C3a ics allergic reaction (3). Two types of pseudoaller- and C5a anaphylatoxins, triggering mast cells and gy have been traditionally defined: intolerance and basophils for secretory response. As a result, there idiosyncratic reaction. The pathogenesis of these is an excessive amount of C3 and C5 anaphyla- reactions includes pseudoallergy, idiosyncratic re- toxins in the circulation, which can have dramatic actions, IgE mediated hypersensitivity, and also cardiovascular sequels (6,7). A new proposal has elevated IgG antibodies. Pseudoallergy is some- been given in recent literature to fit CARPA in the times called drug intolerance. Clinical symptoms classic scheme of hypersensitivity reactions, ac- are practically identical to IgE-mediated immedi- cording to the basic mechanism of mast cell and ate type symptoms and include angioedema, ur- basophil activation. There are direct and receptor- ticaria, bronchospasm, gastrointestinal signs and mediated reactions and therefore there are true anaphylaxis (previously called anaphylactoid re- IgE-mediated allergy, anaphylatoxin-mediated action). Probably the same effector mechanisms CARPA and IgE plus anaphylatoxin double trig- and cells (basophils and mast cells) are involved. gered reactions (6,7). However, since there is no evidence for induction Such reactions are primarily caused by 1) cer- of specific immunologic parameters, skin tests tain liposomal formulations of intravenous drugs and antibody determinations are typically negative and imaging agents; 2) infusion liquids contain- (3). The most common nonallergic reactions are ing micelle-forming amphiphilic lipids or synthetic to nonsteroidal antiinflammatory drugs (NSAIDs) block-copolymer emulsifiers; and 3) iodinated ra- and hypersensitivity to angiotensin-converting en- diocontrast media with limited solubility in water. zyme (ACE) inhibitors. Some reactions to drugs According to recent literature data, intravenous are due to an enzyme defect or deficiency. This application of some liposomal drugs, radiographic is observed in severe hypersensitivity reactions to agents used in diagnostic procedures, micelles or sulfonamides and aromatic anticonvulsants (4,5). other types of lipid-based nanoparticles can cause Drug intolerance is a condition encountered in acute hypersensitivity reaction in up to 45% of pa- patients that are unable to metabolize a drug due tients. The mechanism of these reactions is acti- to a defect or lack of the normal enzyme involved vation of the complement system on the surface of in the respective drug pharmacology; this results lipid particles. in an unexpected reaction to a specific drug. An example of intolerance is deficiency of glucose-6- Table 1. Three different groups of medications with phosphate dehydrogenase and methemoglobin- capacity of causing complement-activation related emia as the result of the use of dapsone. nonallergic hypersensitivity reaction (according to Today, there are new insights in the pathomecha- Szebeni et al.) nisms of these reactions, and some of them have Complement-activated nonallergic hypersensitivity been more or less clarified. reactions 1) Liposomal formulations of intravenous drugs and TYPES OF DRUG REACTIONS imaging agents 2) Infusion liquids with micelle-forming amphiphilic Modern pharmacotechnology has made great lipids or synthetic block-copolymer emulsifiers effort to increase therapeutic index of drugs by us- 3) Iodinated radiocontrast media with limited water ing nanoparticulate vehicle systems. These sys- solubility tems are used to provide slow release or targeted ACTA DERMATOVENEROLOGICA CROATICA 55 Jurakić Tončić et al. Acta Dermatovenerol Croat Nonallergic hypersensitivity to different drugs 2009;17(1):54-69 These acute reactions manifest with severe he- bation with human plasma (9). Recent literature modynamic, respiratory and cutaneous changes data point to the role of lipoproteins in complement (8). For example, a drug named paclitaxel (Taxol®) activation-related nonallergic hypersensitivity activates complement system in human serum in caused by amphiphilic drug carriers (10). Comple- vitro, due to fact that dilution of the injection con- ment activation requires multiple complement and centrate in aquagenous solvents resulted in mi- other immune proteins on the activator surface. As celle formation and needle like structures with final mentioned above, Cremophor EL micelles or po- result of complement activation (9). loxamer 188 individual molecules when exposed Cremophor EL is the main component of mi- to plasma cause de novo formation of abnormally celles and is used as a nonionic emulsifier. These large lipoprotein-like structures. Therefore, this micelles were shown to be 8-22 nm in diameter lipoprotein transformation may be the key event when analyzed, but de novo formation of micro- in complement activation caused by amphiphi- droplets sized 50-300 nm occurred following incu- lic emulsifiers. Lipoproteins also have a negative Table 2. Groups of medications,