Special Focus Review
Drug allergy: Causes and desensitization
Keywords: Drug Allergy, desensitization, drug allergy pathogenesis
Authors: Richard Warrington
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Abstract:
Allergic drug reactions occur when a drug, usually a low molecular weight molecule, has the ability to stimulate an immune response. This can be done in one of two ways. The first is by binding covalently to a self-protein, to produce a haptenated molecule that can be processed and presented to the adaptive immune system to induce an immune response. Sometimes the drug itself cannot do this but a reactive breakdown product of the drug is able to bind covalently to the requisite self-protein or peptide. The second way in which drugs can stimulate an immune response is by binding non-covalently to antigen presenting or antigen recognition molecules such as the major histocompatibility complex (MHC) or the T cell receptor. This is known as the p-I or pharmacological interaction hypothesis. The drug binding in this situation is reversible and stimulation of the response may occur on first exposure, not requiring previous sensitization. There is probably a dependence on the presence of certain MHC alleles and T cell receptor structures for this type of reaction to occur.
Allergic drug reactions occur when a drug, usually a low molecular weight molecule, has the ability to stimulate an immune response. This can be done in one of two ways. The first is by binding covalently to a self-protein, to produce a haptenated molecule that can be processed and presented to the adaptive immune system to induce an immune response. Sometimes the drug itself cannot do this but a reactive breakdown product of the drug is able to bind covalently to the requisite self-protein or peptide. The second way in which drugs can stimulate an immune response is by binding non-covalently to antigen presenting or antigen recognition molecules such as the major histocompatibility complex (MHC) or the T cell receptor. This is known as the p-I or pharmacological interaction hypothesis. The drug binding in this situation is reversible and stimulation of the response may occur on first exposure, not requiring previous sensitization. There is probably a dependence on the presence of certain MHC alleles and T cell receptor structures for this type of reaction to occur.
There is increasing evidence for the need for specific MHC alleles to be present in order for drug reactions to occur. This requirement varies between ethnic groups and may be limited to certain drugs and certain forms of hypersensitivity reactions, such as Stevens-Johnson/ Toxic epidermal necrolysis. It has also become more evident that there is an interaction between drug hypersensitivity reactions and viral infections, best known with the maculo-papular rashes occurring with amino-penicillins but clearly demonstrated in the Drug-induced Hypersensitivity Syndrome, where an interplay of drug-induced immune responses and Herpes viruses occurs. There is increasing evidence for the ability of drugs to initiate immune responses through activation of the innate immune system. In addition, drug reactions can appear to involve the adaptive immune system when in fact the manifestations are due to direct effects upon mediator-containing cells such as mast cells, or other inflammatory systems such as prostaglandin/leukotrienes and the kinin system.
In the presence of drug hypersensitivity, it is sometimes necessary to re-institute administration of the implicated drug because no satisfactory alternatives are available. There have been significant advances in such techniques, particularly for reactions considered to be immediate or anaphylactic in type, and there is increased understanding of the mechanisms that may be involved in desensitization. However many drug reactions appear to involve cell-mediated immune responses, and while desensitization in milder forms of drug hypersensitivity is performed, little s known of the mechanisms involved.
Adverse drug reactions are frequently classified into two types. Type A reactions are common and are caused by the pharmacologic or toxic effects of the drug. Type B reactions are uncommon and unpredictable, occurring in susceptible and predisposed individuals. These include allergic drug reactions, making up about 15% of all adverse drug reactions.1
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