immunology allergic disorders
Drug Hypersensitivity
Pathophysiology of Drug Hypersensitivity
Some protein and large polypeptide drugs (eg,insulin, therapeutic antibodies) can directly stimulate antibody production. However, most drugs act as haptens, binding covalently to serum or cell-bound proteins, including peptides embedded in major histocompatibility complex (MHC) molecules. The binding makes the protein-drug complex immunogenic, stimulating antidrug antibody production, T-cell responses against the drug, or both. Haptens may also bind directly to class II MHC molecules, directly activating T cells. Some drugs act as prohaptens. When metabolized, prohaptens become haptens; eg, penicillin itself is not antigenic, but its main degradation product, benzylpenicilloic acid, can combine with tissue proteins to form benzylpenicilloyl (BPO), a major antigenic determinant. Some drugs bind and stimulate T-cell receptors (TCR) directly; the clinical significance of nonhapten TCR binding is being determined. How primary sensitization occurs and how the immune system is initially involved is unclear, but once a drug stimulates an immune response, cross-reactions with other drugs within and between drug classes can occur. For example, penicillin-sensitive patients are highly likely to react to semisynthetic penicillins (eg,amoxicillin, carbenicillin, ticarcillin). In early, poorly designed studies, about 10% of patients who had a vague history ofpenicillinsensitivity reacted to cephalosporins, which have a similar beta-lactam structure; this finding has been cited as evidence of cross-reactivity between these drug classes. However, in recent, better-designed studies, only about 2% of patients with apenicillinallergy detected during skin testing react to cephalosporins; about the same percentage of patients react to structurally unrelated antibiotics (eg, sulfa drugs). Sometimes this and other apparent cross-reactions (eg, between sulfonamide antibiotics and nonantibiotics) are due to a predisposition to allergic reactions rather than to specific immune cross-reactivity. Penicillin allergy does not always rule out use of cephalosporins. 