TOXICITY UNRELATED TO A DRUG’S PRIMARY PHARMACOLOGIC ACTIVITY _ Immunologic Mechanisms

 

Most pharmacologic agents are small molecules with low molecular weights (<2000) and thus are poor immunogens. Generation of an immune response to a drug therefore usually requires in vivo activation and covalent linkage to protein, carbohydrate, or nucleic acid.

Drug stimulation of antibody production may mediate tissue injury by several mechanisms. The antibody may attack the drug when the drug is covalently attached to a cell, and thereby destroy the cell. This occurs in penicillin-induced hemolytic anemia. Antibody-drug-antigen complexes may be passively adsorbed by a bystander cell, which is then destroyed by activation of complement; this occurs in quinineand quinidine-induced thrombocytopenia. Heparin-induced thrombocytopenia arises when antibodies against complexes of platelet factor 4 peptide and heparin generate immune complexes that activate platelets; thus the thrombocytopenia is accompanied by “paradoxical” thrombosis and is treated with thrombin inhibitors. Drugs or their reactive metabolites may alter a host tissue, rendering it antigenic and eliciting autoantibodies. For example, hydralazine and procainamide (or their reactive metabolites) can chemically alter nuclear material, stimulating the formation of antinuclear antibodies and occasionally causing lupus erythematosus. Autoantibodies can be elicited by drugs that neither interact with the host antigen nor have any chemical similarity to the host tissue; for example, the antihypertensive α-methyldopa frequently stimulates the formation of antibodies to host erythrocytes, yet the drug neither attaches to the erythrocyte nor shares any chemical similarities with the antigenic determinants on the erythrocyte. Drug-induced pure red cell aplasia is due to an immune-based drug reaction. Red cell formation in bone marrow cultures can be inhibited by phenytoin and purified IgG obtained from a patient with pure red cell aplasia associated with phenytoin.

Serum sickness results from the deposition of circulating drug-antibody complexes on endothelial surfaces. Complement activation occurs, chemotactic factors are generated locally, and an inflammatory response develops at the site of complex entrapment. Arthralgias, urticaria, lymphadenopathy, glomerulonephritis, or cerebritis may result. Foreign proteins (vaccines, streptokinase, therapeutic antibodies) and antibiotics are common causes. Many drugs, particularly antimicrobial agents, ACE inhibitors, and aspirin, can elicit anaphylaxis, with production of IgE, which binds to mast cell membranes. Contact with a drug antigen initiates a series of biochemical events in the mast cell and results in the release of mediators that can produce the characteristic urticaria, wheezing, flushing, rhinorrhea, and (occasionally) hypotension.

Drugs may also elicit cell-mediated immune responses. Topically administered substances may interact with sulfhydryl or amino groups in the skin and react with sensitized lymphocytes to produce the rash characteristic of contact dermatitis. Other types of rashes may also result from the interaction of serum factors, drugs, and sensitized lymphocytes.

Source: Harrison_s_Principles_of_Internal_Medicine_16th_Edition