Mechanisms of allergic and allergic-like reactions to drugs and therapeutics
The exact mechanism involved in most reactions to drugs and therapeutic agents is unknown. Fully 90% of adverse reactions fall into the drug intolerance group. Of those reactions that are classified as a drug allergy, the best-studied reactions are those to p-lactam antibiotics, particularly penicillin and insulin.
Drug Reactions Usually Involving immunoglobulin E or Other Immunological Mechanisms
b-Lactam Antibiotics
b-lactam antibiotics include the penicillins, cephalosporins, carbapenems, and monabactams. Penicillin and cephalosporin each have a b-lactam ring. Carbapenems and monabactams also share this ring structure.
Overview of Adverse Drug Reactions
• Most reactions do not involve immune events.
• A skin rash is the most common type of drug reaction.
• Most drug reactions occur in adult females and those individuals who are frequently intermittently exposed to multiple medications.
• More allergic drug reactions occur to p-lactam antibiotics than to other antibiotics.
• Reactions to radiocontrast media and aspirin/nonsteroidal anti-infl ammatory agents are frequent causes of allergic-like or nonimmunological reactions.
In the human body, penicillin is metabolized to form various products. Most of the parent drug is broken down into penicolloyl, which readily combines with a carrier protein to become a complete antigen. This is called the major determinant (most common metabolic by-product). The remainder of penicillin stays either in its native state or is metabolized to other chemical structures, such as penicilloate. These agents, coupled with a protein, are referred to as minor determinants (less common metabolic by-products). The ease with which these penicillin metabolites and the parent penicillin couple to tissue proteins is believed to be important in why these drugs are so often involved in allergic reactions and other drugs are not.
Of individuals who have become allergic to penicillin, most develop type I immunoglobulin E-specific reactions to the major determinant, and an urticarial (or maculopapular/ morbilliform) rash is the usual manifestation. In individuals sensitized to the minor determinant, specific systemic anaphylaxis is more of a risk.
In addition to allergies that develop the p-lactam ring side-chain chemical structures of either the penicillins or cephalosporins may elicit the production of immunoglobulin E-allergen specific antibodies, which are clinically significant. Individuals, particularly in Europe, have been identified with allergic reactions to ampicillin, amoxicillin or individual cephalosporin, but not to penicillin. These reactions have been referred to as p-lactam antibiotic side-chain hypersensitivities. In the case of the monabactams, if immunoglobulin E antibodies do develop, they are likely aresult of side-chain specifics. Recent surveys have shown that side-chain hypersensitivities are relatively uncommon among p -lactam-aller-gic individuals living in North America.
Penicillin and other β-lactam antibiotics may also be responsible for a type II or type III immune reaction. Immune hemolytic anemia can result from the binding of the drug or its metabolites to the surface of a red cell, followed by a specific antibody-mediated cytotoxic reaction that is directed against the drug antigen or at the cell membrane component altered by the drug. This reaction and immune throbocytopenia may occur with other drugs as well.
In type III immune reactions, soluble immune complexes are responsible for the syndrome of serum sickness. Although originally this term depicted reactions to “horse serum,” penicillin and other β-lactams as well as other drugs can react in a serum sickness-like fashion. Clinically, events are characterized by fever and a rash that includes a papular urticarial and/or urticarial, lymphadenopathy, and arthralgia, which occur 2-4 wk after the beginning of the drug therapy. At this point, drug and drug antibody immune complexes are in slight antigen excess, and the complement system is activated. Clinical symptoms of serum sickness begin to subside when the drug/metabolites are eliminated from the body by the reticuloendothelial system.
Insulin
Human insulin has a molecular weight of approx 6000, and its amino acid sequence differs from pork insulin by only one amino acid. Insulin is a potent antigen. Approximately 40% of patients receiving porcine insulin therapy develop immunoglobulin E antibodies. These antibodies are almost always directed against the insulin molecule itself, even though animal-derived insulin contains other proteins that may stimulate an immune reaction. Thus individuals can have allergic reactions to human recombinant DNA insulin (alone) and patients with systemic allergy to animal source insulin have positive skin tests to human insulin.
Local reactions to insulin injections are not uncommon but these allergic reaction usually disappear in 3-4 wk of continued administration. Systemic insulin reactions are rare and usually occur when insulin is discontinued and then restarted. Insulin resistance is very rare and related to the development of high titer of IgG insulin antibodies.
Heterologous Serum, Protamine and Vaccines
Animal serum exposure (e.g., horse serum in snake bite antivenom) may be responsible for immunoglobulin E-mediated anaphylaxis in individuals presensitized to these animals. Horse serum may also cause serum sickness.
Protamine is a low molecular weight protein derived from the sperm of salmon. immunoglobulin E sensitizations and subsequent reactions occur in 0.05-10% of individuals where protamine used frequently (e.g., diabetics using NPN insulin).
Although infrequent, systemic allergic reactions, do occur to vaccines. Most of these reactions are now felt to be a result of immunoglobulin E antibodies directed against porcine gelatin used as a stabilizer in these vaccines. Gelatin is found in various amounts in measles, mumps and rubella, varicella, rabies, Japanese encephalitis, influenza, and DTP vaccines.
Previously, chicken egg allergy was thought to be a risk in individuals who required mumps and rubella vaccine immunization. However, measles and mump vaccines are grown on chicken embryo fibroblasts, which contain little or no egg protein. Mumps and rubella has been shown to be safe for administration in egg-allergic individuals. Influenza and yellow fever vaccines are grown on egg products, and therefore the final product contains enough egg protein to potentially induce and immunoglobulin E allergic reaction in chicken-egg-allergic individuals.
Blood or Blood Products
Reactions to blood transfusions may be a result of hemolysis secondary to the use of ABO-incompatible blood products. Patients with this type of reaction develop fever, chills, low blood pressure or shock, back pain, and hemoglobinuria within 1-2 h after a transfusion. Isolated transfusion fever can occur from the presence of interleukin (IL)-1,6, and 8 and tumor necrosis factor (tumor necrosis factor)-a in the blood products. Urticaria (1-3 per 100) wheezing (1-2 per 1000), or anaphylaxis (1-20 per 50,000) reactions have been reported with the transfusion of blood products, usually as a result of complement activation and release of C3a and C5a. Individuals with 1g A deficiency (as common as 1:700) may develop immunoglobulin E antibodies to IgA and therefore are at risk for an allergic reaction when given blood products.
Monoclonal Antibodies
New biological agents are now available and more are being developed to treat many disease conditions. In some cases, allergic-like reactions have occurred (including anaphylaxis or anaphylactoid reactions and serum sickness-like reactions). Although the exact mechanism of these events is often not clear, the potential for immunoglobulin E antibodies development exists.
Sulfonamides and other antimicrobial agents
In their native state, sulfonamides are not immunologically reactive. However, with metabolism, the breakdown products of these drugs have the potential to react with carrier proteins and become complete antigens and induce immunoglobulin E antibodies. In general, however, most drug reactions (usually a rash) induced by sulfonamides are not felt to be a result of immunoglobulin E or other immune events. Recent studies indicate that individuals with a history of sulfonamide antibiotic rash are not at risk for reactions to sulfa-containing nonantibiotic drugs because of cross-sensitivity.
Vancomycin antibiotic intravenous infusion has been responsible for generalized flushing, the so-called red-man syndrome. The mechanism of reaction in this case thought to be related to direct toxic release of histamine from mast cells/basophiles. Rare cases of vancomy-cin-immunoglobulin E-antibody-induced anaphylaxis have been reported.
Urticaria and other anaphylactoid reactions have been reported to occur in 1.2/100,00 prescriptions of ciprofloxin (a quinolone). Most of these reactions occur with the first administration of the antibiotic and are not a result of immunoglobulin E antibodies.
In the case of rash due to either macrolide or tetracycline antibiotics, they tend to be mild and not immunoglobulin E mediated. A photosensitivity may occur with the use of some tetracyclines.
Aspirin nonsteroidal anti-inflammatory drugs, and Selective Cyclooxygenase-2 Inhibitors
Aspirin (ASA) and nonsteroidal anti-inflammatory drugs may both cause or exacerbate urticaria/angioedema and anaphylactoid reactions. They are one of the most common reasons for drug-induced urticaria in adults. These drugs are responsible for a syndrome consisting of perennial rhinitis, sinusitis, nasal polyps, and severe asthma. Current studies indicate an important role for increased leukotriene production (especially LTC4, LTD4, and LTE4), kininogen, and histamine release in these allergic-like reactions. immunoglobulin E antibodies against aspirin or nonsteroidal anti-inflammatory drugs have not been identified. Most, if not all these reactions resulting in asthma are felt to be related to inhibition of the cyclooxygenase (cyclooxygenase)-l products (ASA is both a cyclooxygenase-1 and cyclooxygenase-2 inhibitor). Recently, cyclooxygenase-2 inhibitor drugs have been developed mainly to reduce the possible undesirable side effect of G.I bleeding produced by ASA use. Studies have shown that cyclooxygenase-2 inhibitor agents are generally safe in asthmatics reactive to ASA or NS AIDs. However, there are reports of patients who have had urticaria or anaphylactoid reactions to ASA or nonsteroidal anti-inflammatory drugs who have reacted to one or more cyclooxygenase-2 inhibitor drugs for unknown reasons.
Radiocontrast media
The imaging efficacy of radiocontrast media depends upon the iodine concentration that can be delivered to a space within the body. Since radiocontrast media was first discovered in 1923, the character of the iodinated compound has progressed from a monoiodinated to a tri-iodinated benzoic acid compound. The conventional radiocontrast media is hypertonic, having osmolarity up to six times that of plasma. A newer, nonionic radiocontrast media has been developed that has an osmolarity less than 50% of the conventional material and retains the same iodine concentration. This change in osmolarity of the newer radiocontrast media material has reduced the vascular wall toxicity and allergic-like reactions with the use of these agents, presumably by reducing the capacity of the newer agent to form bonds with body proteins.
The exact mechanism by which radiocontrast media elicits an anaphylactoid reaction is unknown. However, in vitro histamine release does occur, probably through direct interaction between radiocontrast media and a cell membrane receptor. Unfortunately, there is no consistent documented relationship between histamine release by these agents and clinical adverse events.
Radiocontrast media can activate the complement system. Conventional radiocontrast media has been shown to have a direct effect on C3 and C4 to produce C3b and C4b anaphylatoxins (which in turn can cause histamine release). The newer low-osmolarity radiocontrast media has been shown to activate complement through the alternate pathway by inhibition of factors H and I. The exact role activation of complement by either conventional or the newer radiocontrast media agents plays in the production of an anaphylactoid reaction is still speculative.
Angiotensin-Converting Enzyme Inhibitor Drugs and Angiotensin II Receptor Antagonist Drugs
Angiotensin-converting enzyme inhibitor (angiotensin-converting enzyme-IN) drugs may produce cough or angioedema (anaphylactoid reactions) in different groups of patients. Cough occurs as frequently as in 10-25% of patients, usually starting within the first 8 wk of use, but occasionally as late as 1 yr. It usually disappears within 1-2 wk after discontinuing the medication.
Severe angioedema of the face, mouth or throat may occur in 1-2/1000 patients and can be life threatening. This may occur within the first week or as late as several years of therapy. The risk of angioedema is greater with the use of these agents in African Americans and in patients with hereditary angioedema, idiopathic urticaria/angioedema, or idiopathic anaphylaxis.
Although the mechanism of these reactions is not entirely clear, increased histamine release, inhibition of bradykinin degradation, and abnormal prostaglandin and substance P metabolism are suspected.
There appears to be less cough associated with the use of angiotensin II receptor antagonist (A-II RAS) drugs. However, in patients who have had angioedema with a specific angiotensin-converting enzyme-IN drug, switching to another angiotensin-converting enzyme-IN agent or use of an A-II RAS does not decrease the risk of reaction and is not advised.
General and Local Anesthetics
Systemic allergic-like reactions during general surgery are usually secondary to anaphylaxis to muscle relaxants such as succinylcholine or isoquinolones. The incidence of anaphylaxis is 1 in 5000-15,000 procedures with a mortality rate of approx 5%. Half of these reactions are felt to be owing to immunoglobulin E antibodies, but one-third occur without previous exposure to muscle relaxants and may be a result of direct histamine release.
Fairly frequently, the allergist is called upon to evaluate an individual who has a reaction to local anesthetics. Rarely are these a result of an immunoglobulin E mechanism, and they are either toxic, psychologic, or neurologic in nature. Often reactions are the result of concomitant administration of epinephrine in the drug preparation added to reduce the absorption of the local anesthetic.
Chemotherapeutic Agents
Allergic-like adverse reactions to many agents used in cancer therapy have been reported. The risk is greatest with repeated use of L-aspariginase (up to one-third of cases). Urticaria or asthma may occur within 1 h of administration. Similar reactions have been reported with the use of taxanes. Although an immunoglobulin E mechanism has been suspected, none has been proven.
Carboplatin has been shown to be associated with anaphylaxis in 30% of patients after multiple cycles of intravenous therapy, typically on the eighth cycle. These reactions are believed to be immunoglobulin E mediated based upon a negative immunoglobulin E id skin test of undiluted drug in nonreactive patients and positive skin test in reactive individuals.
Opiate Drugs
Urticaria or anaphylactoid reactions can occur in otherwise normal individuals upon exposure to morphine, codeine, or synthetic opiates. These reactions are usually caused by direct action of the drug on the mast cell to release mediators, rather than an immunoglobulin E mechanism.
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