Nghia H. Pham

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.

Immunoglobulin E binding determinants on beta-lactam drugs.

Purpose of reviewAllergies to penicillins and cephalosporins remain an important clinical problem, but structural and immunochemical knowledge of the allergenic structures involved has tended to lag behind the heavy usage, consequent adverse reactions and introduction of new therapeutic members of these two families of antibiotics. Evidence of the increasing incidence of reactions to cephalosporins and to ‘minor’ determinants of the β-lactams is accumulating. Also, although numerous reports detail unique allergic recognitions of individual members of the two families, particularly the cephalosporins, information remains predominantly clinical. The present review summarizes the most recent advances in studies of structural aspects of β-lactams as allergens. Recent findingsFor the cephalosporins, a pyrazinone allergenic degradation product of cefaclor and cephalexin has been identified and characterized. The widely used cephalosporin cephalothin was shown to cross-react allergenically with benzylpenicillin and the common cross-reacting structure was identified. The fine structural features on the amoxicillin molecule recognized by antibodies that distinguish ‘major’ and ‘minor’ determinants were identified, and steric factors were used to explain antibody recognition of the amoxicillin determinants. A recent study elucidated the molecular basis of some cases of the multiple drug allergy syndrome and its relationship to β-lactam allergy. SummaryFindings of the type described in the present review provide fundamental insights into the nature and size of antigenic determinants on ‘small’ molecules such as drugs and other chemicals. At the clinical level, such structure/activity findings have implications for our understanding of drug allergenic cross-reactions, for selection for therapy of an appropriate member from a family of structurally related drugs and, ultimately, for desensitization of drug-allergic patients.

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.

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.

Proton Pump Inhibitors

PPIs, omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, and dexlansoprazole bind irreversibly to the H+, K+-ATPase (the “proton pump”) inhibiting its activity and decreasing gastric acid production. Systemic reactions to PPIs include anaphylaxis, urticaria, angioedema, interstitial nephritis, and thrombocytopenia. Cutaneous reactions include contact dermatitis, maculopapular and lichenoid eruptions, vasculitis, exfoliative erythroderma, AGEP, DRESS, and SJS/TEN. Autoimmune reactions, including cutaneous lupus erythematosus, have been described. Cross-reactions between PPIs may be limited to one or two drugs, or all drugs may be recognized. Cross-reaction studies so far have been based on skin testing, but the interpretations lack a quantitative basis. Successful oral desensitization following anaphylaxis to a PPI has been achieved in a few hours. Skin testing and challenge testing have been the only procedures employed to routinely diagnose immediate reactions to PPIs. A suitable test for the detection of PPI-specific IgE antibodies is not yet available, and application of the basophil activation test has been limited. A surprising number and diverse range of PPI-related adverse events have been reported. PPI-induced adverse events can be divided into those related, and those unrelated, to acid inhibition. There appears to be a relationship between gastric acid suppression and development of allergic symptoms.

Drugs and Other Agents Used in Anesthesia and Surgery

Neuromuscular blocking drugs (NMBDs) are the most common cause of anaphylaxis during anesthesia representing ~60 % of reactions and an incidence of 1 in 1,000–20,000. Reactions are mediated by IgE antibodies with specificity for tertiary and quaternary ammonium ions, but adjoining structures may also be recognized. Recognition of the substituted ammonium groups accounts for the extensive cross-reactivity between the NMBDs. Diagnosis of reactions is effected by skin testing with free drugs, IgE antibody assays (especially using a morphine-solid phase), and the tryptase assay. Reversal of rocuronium-induced NM block with the cyclodextrin sugammadex has highlighted the question of changed allergenicity of such chemically sequestered drugs in host–guest complexes. Anaphylactic reactions to the hypnotics thiopentone and propofol are rare. Both are diagnosed by skin testing and the former also by a specific IgE test. True IgE-mediated reactions to local anesthetics are extremely rare; many reactions appear to be vasovagal responses, but delayed reactions are well known. Anaphylactic and other adverse reactions occasionally occur to colloids such as hydroxyethyl starch, gelatin, and dextrans, to the polypeptides protamine and aprotinin, and to heparins and patent blue V. Pre-injection of small MW dextran 1 reduces the incidence of dextran-induced anaphylaxis from 25 to 3 per 100,000.

Adverse Reactions to Drugs and Drug Allergy: Scope of This Book

In what is essentially a pharmacologically based classification of adverse drug reactions (ADRs), unpredictable and dose-independent drug reactions, designated type B reactions, include hypersensitivity responses while those reactions designated as type A are predictable, dose-dependent, and make up about 80 % of all ADRs. Previous exposure is not always a prerequisite for allergic sensitization, and there are many instances where reactions occur after initial contact with poorly reactive drugs that do not bind to proteins. Risk factors for drug allergy can be divided into those that are patient-related (age, sex, current diseases, previous exposure, genetic factors) and those that are drug-related (nature and cross-reactivity of drug, degree of exposure, route of administration). Genomic studies are already helping to explain some ADRs, for example, the association in Han Chinese of carbamazepine-induced Stevens–Johnson syndrome with HLA-B*15:02 and the association of abacavir hypersensitivity in abacavir hypersensitivity syndrome with HLA-B*57:01. It seems likely that multiple rather than single genes are involved in ADRs. Drug allergy studies promise to provide significant insights into important areas of biomedical investigation including cell recognition and interaction processes, relationships between receptors and effector pathways and mechanisms of mediator actions.