400 Anaesthesia and allergic drug reactions G. C. Moudgil MB M SC FFARCSFRCPC An allergic drug reaction, by definition, is an Compounds of low molecular weight (500-1000) untoward physiologic response produced by an are incapable ofeliciting antibody formation, and as immunologically mediated reaction. Although a such are incomplete antigens or haptens. wide variety of factors such as physico-chemical Most drugs, their metabolites, and preservatives interaction, enzyme induction or inhibition, drug such as methyl paraben are incomplete antigens. overdose or toxicity, may all contribute toward Only after conjugation with a protein called a adverse drug reactions, these should be distin- "carrier" do they become allergenic or immuno- guished from immunologically mediated allergic genic. 3 For this to occur a stable covalent bond is drug reactions that occur capriciously and explo- essential.4 The commonly observed pharmacologic sively, with little or no warning. Contrary to binding of drugs to the serum proteins is too weak to the common belief, allergic reactions are not rare. render them immunogenic. Immunogenicity may In the United States of America, approximately be accomplished when a drug contains a chemically 200,000 patients suffer an allergic drug reaction reactive group such as an anhydride or a quinone. each year during their stay in the hospital. Another Alternatively, a spontaneous or enzymatic conver- one million people probably experience milder sion of the drug in the body may also create reactions that do not require hospital treatment. 1 It chemically reactive groups that are likely to render has been estimated that one of every six patients it immunogenic. requiring medical treatment has suffered a true or Exposure to such drugs or chemically similar suspected allergic reaction to a drug at some time. J substances results in the production of antibodies The use of a greater number of drugs in the such as immunoglobulin E (IgE), immunoglobulin perioperative period has resulted in an enhanced G (IgG), and immunoglobulin M (IgM), by the incidence of allergic drug reactions during anaes- plasma cells. Subsequent exposures to these drugs thesia, z Since allergic drug reactions are potentially may cause an antigen-antibody reaction which life threatening, their prompt recognition and treat- releases pharmacologically active mediators re- ment are essential for the patient's survival and well sponsible for the ultimate adverse effects. Previous being. Therefore, an understanding of the patho- uneventful single or repeated exposures to the same genesis, clinical manifestation, diagnosis, treat- or similar drugs do not negate the possibility of a ment and prevention of allergic drug reactions is severe allergic response on subsequent exposures. 5 essential for better patient care and management. In addition to immune system mediated allergic reactions, where a previous exposure to the drug is Pathogenesis of allergic drug reactions mandatory, drug reactions may also occur by a The ability of the body to recognize and respond to direct effect of the drugs on the effector ceils. These the "non self" forms the basis of the immune non-immunologic drug reactions have been classed response. Following exposure to a foreign sub- as anaphylactoid reactions and their clinical mani- stance (an antigen), the body may either develop festations are indistinguishable from the immune specific serum protein molecules called antibodies, mediated allergic reactions. or produce immunologically sensitized lympho- cytes. The production of antibodies and the subse- quent antigen-antibody reaction forms the basis of From the Department of Anaesthesia, McMaster Univer- humoral immunity, whereas the induction of sensi- sity Medical Centre, 1200 Main Street West, tized lymphocytes is called cellular immunity. Hamilton, Ontario, LSN 3Z5. CAN ANAESTH SOC J 1986 / 33: 3 I pp400-14 Moudgil: ANAESTHESIA AND ALLERGIC DRUG REACTIONS 401 Classification of allergic reactions by the dose and the affinity of the drug for the lgE Allergic drug reactions may be subdivided into antibodies, the number of cell-bound IgE antibodies immune system mediated "anaphylactic reactions" and the intracellular concentration of cyclic nucleo- and non-immune direct responses called "anaphyl- tides. ~o Degranulation and the subsequent release actoid reactions." of chemical mediators is an energy dependent process which results in a substantial fall of the Immune system mediated drug reactions intracellular ATP levels. The clinical expressions of More than twenty years ago Gell and Coombs type I hypersensitivity include anaphylaxis, extrin- described the following four basic types of allergic sic asthma and extrinsic rhinitis. reactions that are mediated by immune processes. 6 TYPE I1 - CYTOTOXICHYPERSENSITIVITY TYPE I - ANAPHYLACTICOR IMMEDIATE This reaction is caused by an IgG or IgM antibody HYPERSENSITIVITY that is directed at the cell surface antigen. The A previous exposure to the same, or a similar antigens may be an integral part of the cell mem- pharmacologic agent is necessary for this type of brane, e.g., A or B blood group antigens or they reaction to occur. The earlier exposure to the may be surface adsorbed haptens which stimulate pharmacologic agent results in the production of an antihapten antibody production. Following anti- antibody of the IgE immunoglobin class. The gen-antibody interaction, contact with phagocytes principal site of IgE synthesis is in the lymphatic is enhanced by a reduction in surface charge, and by tissue of the respiratory and gastrointestinal sys- opsonic or immune adherence through the mem- tems, with tonsils and adenoids being particularly brane bound complement protein C3. As a result of rich in IgE forming plasma cells. The IgE antibody this increased cell adherence, cell death is enhanced because of its specific affinity, binds on to the by phagocytosis. Cell damage may also result surface receptors of basophils and mast ceils. The following the complete activation of the comple- IgE receptor is a glycoprotein with molecular ment system. The classical complement system weight of approximately 50,000. 7 The receptor is consists of nine separate components numbered C1 an integral component of the cell membrane of to C9, that on activation interact sequentially with basophils and mast cells and is not seen on any other one another in a cascade fashion (Figure). The types of leucocytes, s It has been estimated that between 40,000 and 100,000 IgE receptors are present on human basophils. The binding of IgE C1 Ab-Ag with its receptor is temperature dependent, quite CT specific, and not affected by immunoglobulins of C4 + C2 ) C~ + Fragments with kinin-like activity other classes. 9 Once the antibodies have been bound to mast cells and basophils, these cells are C3b + C3a ready to participate in the immediate hypersensi- Enhanced Anaphylatoxin tivity reaction upon appropriate antigenic stimula- phagocytosis Chemotactic tion. Such an allergenic stimulus is provided by a C5 C,.,.2.} C~b + C5, re-exposure to the same or similar drug. The drug Anaphylatoxin forms a bridge across the two cell-bound lgE Chemotactic antibody molecules and cross-links them. The Csb cross-linking induces a membrane change which C~ + C7 ) C5,6.7 results in an influx of calcium ions and changes in Chemotactic cyclic nucleotide levels. A fall in cyclic 3',5'- C8 + C9 C$'6'7 i, C$.6,7,8,9 adenosine monophosphate (cAMP) or a rise in Cytolysis cyclic 3',5'-guanosine monophosphate (cGMP) fa- CL-C_.9= Components of complement system. vours mast cell degranulation and mediator release, Ab-Ag = Antibody-antigen complex, whereas high concentrations of cAMP stabilize the Bars above numbers indicate activated complementcomponents. mast cell granules. The extent of cellular degranulation is influenced FIGURE Flowdiagram of complement cascade 402 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL complement system, once activated is probably the observed in response to bacteria, viruses, and in most important source of vasoactive mediators. For rejection of transplanted tissues. However, a wide example, activated complement proteins C3a and range of drugs, cosmetics, soaps and dyes, may Csa are potent anaphylatoxins and leucocyte chemo- cause dermal sensitivity by the mechanisms of attractants.tl The anaphylatoxins Can and C5, re- delayed hypersensitivity. Initially the antigen is lease histamine and other vasoactive substances processed and presented by maerophages to a small from mast cells which produce arteriolar dilatation number of T-lymphocytes which become sensitized and increased vascular permeability. The actual to the antigen. On subsequent contact with antigen damage in Type II reactions results from cell lysis these lymphocytes undergo mitosis, proliferate and either by phagocytosis or through complement produce soluble mediators called lymphokines. system activation. The most common examples of There is also a generation of cytotoxic T-cells. Type II reactions in man are transfusion reactions Temporally the production of the lymphokines is and penicillin induced haemolytic anaemia. the first step to occur and their liberation in vitro can be detected within four hours after the binding of the TYPE III -- IMMUNE COMPLEX-MEDIATED REACTIONS antigen to the previously sensitized T-cells. Lym- Type HI allergic reactions are also lgG and lgM phokines influence the functions of macrophages, mediated reactions and can be subdivided into local polymorphonuclear leucocytes, lymphocytes