Brian A. Baldo

On the origin and specificity of antibodies to neuromuscular blocking (muscle relaxant) drugs: an immunochemical perspective

Following the demonstration 25 years ago that substituted ammonium groups on neuromuscular blocking drugs (NMBDs) are the main allergenic structures recognized by IgE antibodies in the sera of some patients who experience anaphylaxis during anaesthesia, immunoassays for these drugs were quickly applied to supplement skin tests in the diagnostic assessment of suspected adverse reactions to anaesthetic agents. Many subjects who react to an NMBD do so on first exposure and this led to the speculation that the origin of allergic sensitization is an environmental agent(s) or another drug containing an ammonium ion. Direct antibody binding and hapten inhibition studies revealed that morphine, which contains a tertiary amino group, was strongly recognized by IgE in sera from anaphylactic patients and a morphine‐solid phase immunoassay was found to be superior to NMBD‐based assays for the detection of NMBD‐reactive IgE antibodies. Extensive inhibition experiments indicate the likelihood of antibody combining site heterogeneity with recognition at the fine structural level of features additional, and adjacent to, ammonium ions. Further quantitative investigations are needed to identify these neighbouring groups on different NMBDs. Recent work has implicated the morphine analogue pholcodine as the sensitizing agent in Norway where, unlike Sweden, anaphylactic reactions to NMBDs are not uncommon and the medicament is available over‐the‐counter. This has led to the suggestion that allergenic sensitization to the ammonium group of pholcodine may account for the different incidences of anaphylaxis during anaesthesia in the two countries. This work is subjected to critical review and some alternative speculations on the nature and origin of the sensitizing agent(s) are presented.

Assays for, and cross-reactivities of, IgE antibodies to the muscle relaxants gallamine, decamethonium and succinylcholine (suxamethonium)☆

Two radioimmunoassays have been developed to detect IgE antibodies to succinylcholine, decamethonium and gallamine in the sera of patients who have experienced life-threatening anaphylactoid reactions following administration of a muscle relaxant drug. They involve the coupling of choline and its ethyl analogue, triethylcholine to activated Sepharose. A high degree of cross-reactivity was shown to occur between drug-reactive IgE antibodies and 6 muscle relaxants as well as choline and triethylcholine. Results suggest that the specificities of the IgE antibodies are directed towards quaternary or tertiary ammonium ions on the drugs that bind the antibodies. Molecular models of these compounds support the structure-activity relationships determined in the inhibition studies.

Opioid Analgesic Drugs

Opioid analgesics are one of the most commonly administered groups of drugs in hospitals. These drugs show common structural features, bind specifically to opioid receptors and possess morphine-like pharmacologic action. Tramadol differs from other opioid analgesics in its monoaminergic activity as well as its affinity for the μ opioid receptor. Many opioids are potent histamine releasers producing hemodynamic changes and anaphylactoid reactions, but there seems to be no direct relationship between the histamine plasma concentrations and these changes. True IgE antibody-mediated immediate allergic reactions to opioids are uncommon, although some anaphylactoid reactions are interpreted as allergic, emphasizing the need to investigate whether or not reactions have an immune basis. The histamine-releasing properties of opioid drugs sometimes hamper skin testing, and general unavailability of specific IgE antibody tests contributes to the failure to investigate reactions. Reactions to tramadol, whether anaphylactoid or IgE antibody-mediated, are rare, and the drug is generally considered to be safe with a low potential for adverse reactions. Clinical implications for the diagnosis of opioid drug-induced anaphylactoid and anaphylactic reactions are discussed.

Structural features of allergens large and small with emphasis on recombinant allergens

The application of recombinant DNA techniques to the study of allergen structure has increased our knowledge of primary structures and B- and T-cell determinants. Thus, knowledge of the molecular bases of isoallergens and allergenic cross-reactivities is about to be rapidly expanded. Findings from the early applications of molecular cloning strategies to the study of some polypeptide allergens, together with a summary of our current knowledge of drug allergenic determinants, are presented here.

Nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for 20–25 % of ADRs. Cyclooxygenase isoenzymes COX-1 and COX-2 catalyze the formation of PGG2 from arachidonic acid. Ultimate products of the metabolic pathway are PGD2, PGE2, PGF2α, PGI2, and TXA2. NSAIDs can be classified on the basis of their COX inhibitory and selective properties. Most are mainly COX-1 inhibitory, e.g., aspirin and ibuprofen, while some are COX-2 inhibitory, e.g., celecoxib. NSAIDs with the highest GI toxicity have the highest COX-1 selectivity. COX-2 is expressed in inflammation and selective COX-2 inhibitors show fewer GI effects but can produce cardiovascular effects. The mechanism of NSAID-induced respiratory reactions appears to be due to the redirection of arachidonic acid metabolism from the COX to the lipoxygenase synthetic pathway with associated production of cysteinyl leukotrienes. Aspirin-induced asthma, which makes up 3–5 % of adult asthmatics, has symptoms of chronic asthma, rhinosinusitis, and nasal polyps. NSAID-induced cutaneous reactions occur in a number of different clinical patterns. Challenge testing is the only way to diagnose sensitivity to an NSAID. Desensitization can be induced by repeated oral administration. Delayed reactions are seen and may take the form of contact dermatitis, FDE, DRESS, AGEP, SJS, TEN, or nephritis.

Drugs Used for Chemotherapy

Many of the drugs used for chemotherapy have been, and still are, alkylating agents, antimetabolites, organoplatinum compounds, cytoskeletal disruptors, or anthracyclines, all agents with relatively broad rather than targeted and specific modes of action. The tyrosine kinase inhibitor imatinib mesylate and proteasome inhibitor bortezomib are recent examples of a more specific treatment strategy. Up to 30 % of patients develop acute infusion reactions to taxanes. Hypersensitive cross-sensitivity between docetaxel and paclitaxel is ~90 %. Most reactions to platinum drugs appear after multiple treatment cycles (usually at least six). Reactions are mainly type I or type IV hypersensitivity responses with a few cases of type II and type III hypersensitivities. The drug imatinib mesylate that inhibits both the ABL and BCR-ABL tyrosine kinases has been successful in treating chronic myeloid leukemia. In the chronic phase of treatment, neutropenia results in 35–45 % of cases, thrombocytopenia in 20 %, and anemia in 10 % of cases. Gefitinib and erlotinib are EGFR inhibitors, inhibiting the receptor’s tyrosine kinase domain. Main hypersensitivities to both drugs include cutaneous reactions. GI symptoms, thrombocytopenia, peripheral neuropathy, and neuropathic pain are the most common side effects of the proteasome inhibitor bortezomib. Adverse cutaneous reactions to the drug are numerous.

Classification and Descriptions of Allergic Reactions to Drugs

Four types of hypersensitivities may be distinguished. Type I, or immediate hypersensitivity, occurs within about 30 min, is IgE antibody-mediated, and the allergic signs and symptoms are triggered by cross-linking of mast cell-bound IgE which leads to mast cell degranulation and release of inflammatory mediators. Drugs well known to cause type I reactions include β-lactams, neuromuscular blockers, and some NSAIDs. Anaphylactoid reactions may mimic the signs and symptoms of anaphylaxis but, unlike the latter reactions, anaphylactoid reactions are not immune-mediated. Clinical manifestations of anaphylaxis include erythema, urticaria, angioedema, bronchospasm, and cardiovascular collapse. Urticaria is often associated with angioedema and anaphylaxis. ACE inhibitors are responsible for one in six hospital admissions for angioedema. Types II and III hypersensitivities are known as antibody-dependent cytotoxic and immune complex-mediated hypersensitivities, respectively. Examples of drug-induced type II reactions are hemolytic anemia, thrombocytopenia, and granulocytopenia. A serum sickness-like reaction is the prototype type III drug hypersensitivity. Type IV drug hypersensitivities are mediated by antigen-specific T cells. Reactions occur 48–72 h after antigen exposure and are therefore referred to as delayed. Examples of delayed cutaneous reactions include allergic contact dermatitis, psoriasis, FDE, AGEP, DRESS, SJS, and TEN.

Drugs that Act on the Immune System: Cytokines and Monoclonal Antibodies

Abstract The Side Effects of Drugs Annuals form a series of volumes in which the adverse effects of drugs and adverse reactions to them are surveyed. The series supplements the contents of Meylers Side Effects of Drugs: the International Encyclopedia of Adverse Drug Reactions and Interactions . This review of the January 2012 to June 2013 publications on cytokines and monoclonal antibodies covers bone morphogenetic proteins, colony-stimulating factors, interferons alpha and beta, aldesleukin (interleukin-2) and anakinra (interleukin-1 receptor antagonist), tumour necrosis factor alpha antagonists (adalimumab, certolizumab, etanercept, golimumab and infliximab) and a range of monoclonal antibodies (alemtuzumab, cetuximab, dacetuzumab, daclizumab, efalizumab, gemtuzumab ozogamicin, muromonab, natalizumab, omalizumab, palivizumab, panitumumab, rituximab, teplizumab and trastuzumab). Tumour necrosis factor-alpha antagonists are being used increasingly for inflammatory conditions, such as rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel disease. Post-marketing surveillance is revealing serious and potential life-threatening adverse events.

β-Lactam Antibiotics

The β-lactam antibiotics comprise four main classes of drugs; penams (penicillins), cephems (cephalosporins), monobactams, and carbapenems. Penicillins can cause all four types of hypersensitivity responses. IgE antibodies in patients’ sera detect a spectrum of antigenic specificities, show heterogeneous recognition and cross-reactive responses, and may distinguish fine structural features, e.g., amoxicilloyl and amoxicillanyl determinants. With a negative history of penicillin allergy, the incidence of positive skin tests is 2–7 %. For skin test-positive patients the risk of an acute allergic reaction ranges from 10 % (negative history) to 50–70 % (positive history). IDTs with delayed reading and patch tests are used to diagnose delayed reactions. Aminolysis of cephalosporins produces unstable intermediates that decompose to penaldate and penamaldate structures resulting in only the R1 side chain remaining from the original molecule. With some allergic patients the R2 side chain and/or the whole cephalosporin molecule are also recognized by IgE antibodies. Testing with penicillins does not reliably predict cephalosporin allergy unless the side chains of the penicillin and the culprit cephalosporin are similar. Aztreonam shows little, if any, cross-reaction with penicillins and cephalosporins. The practice of avoiding imipenem and meropenem therapies in penicillin-allergic patients should be reconsidered. There has been an increase in cases of immediate hypersensitivity to clavulanic acid.

Mechanisms of Hypersensitivity

Allergic reactions to drugs are not always the result of the drug’s protein-binding capacity, biotransformation, or degradation. Mediator release may occur via cross-linking of cell-bound IgE by di-(multi-) valent free drug. Physiological and pharmacological effects of histamine are mediated through four receptors, H1, H2, H3, and H4. The H3 receptor has a regulatory role in the release of neurotransmitters such as serotonin and dopamine; the H4 receptor exerts a chemotactic effect on several cell types associated with allergy and asthma. Cysteinyl leukotrienes and PAF are powerful mediators of anaphylaxis, asthma, and shock. Sphingosine-1-phosphate, elevated in the lungs of asthmatics, regulates pulmonary epithelium permeability and contributes to the pathogenesis of anaphylaxis. Urticaria is a heterogeneous disease with many subtypes. Both ACE inhibitors and angiotensin II receptor blockers may cause angioedema. Abacavir changes the shape of the HLA antigen-binding cleft producing an alteration in the repertoire of self-peptides that bind HLA-B*57:01 and a T cell response to self-proteins. Drug-induced delayed-type cutaneous hypersensitivity reactions are mediated by CD4+ and CD8+ CD3+ T cells in the dermis and epidermis. Granulysin appears to be a key molecule for keratinocyte killing in TEN/SJS. Drugs provide good examples of types II (immune hemolytic anemia, drug-induced thrombocytopenia) and III (serum sickness-like) hypersensitivities.