Drug allergy pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

Drug Allergy
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Overview

Medications can cause allergic reactions through various mechanisms. The drug can either act as a direct antigenic particle, or it can cause activation of immune cells by the direct interaction with immune cell receptors.

Pathophysiology

Drugs Acting as Antigens

Most drugs do not act as antigenic particles in their mature form. This is because they are usually small, and therefore not recognized by immune receptors enough to actually activate T cells or B cells. However, drugs can act as antigens if they are presented to lymphocytes by antigen presenting cells such as dendrites. This response specific to the drug can be solely T-cell mediated, antibody mediated, or can have components of both.

• Stimulation of the antibody response- In general, antigens are processed by antigen presenting cells and presented to T-cells. This leads to t-cell activation and produces cytokines which then activate B cells. B cells then recognize the antigen through its IgG receptor, and becomes activated subsequently producing antigen-specific immunoglobulins. Modern pharmaceuticals that are proteins or resemble proteins, can stimulate antibody and T cell responses similar to other protein antigens. Examples of drugs that cause this type of reaction are:
  • insulin
  • enzymes
  • antisera
  • recombinant proteins (monoclonal antibodies)
  • vaccines

Some of these compounds can induce antibody formation without any T cell interaction.

• Drugs as haptens or pro-haptens- Small drugs can become immunogenic by binding covalently to larger macromolecules such as host proteins on cell surfaces or in plasma. The drug is then called a hapten, and the antigenic compound is then called a hapten-carrier complex. These complexes can also induce a a T cell and antibody response. Drugs that give rise to metabolites that can act as haptens are called pro-haptens. For example, penecillin often acts as a hapten when the beta-lactam ring breaks open and reacts with lysine to form a hapten-carrier complex called penecilloyl determinant, which is capable of stimulating T-cells and antibodies . A few drugs which have this capability are
  • penecillin and other beta-lactam antibiotics
  • penecillamine
  • gold and other heavy metals

• Reactive metabolites- Some drugs may not be reactive with macromolecules in their original state, however may form reactive particles after undergoing metabolism by CYP450 enzymes. As part of drug metabolism by hepatocytes, some drugs may not undergo correct detoxification and bind to or haptenate intracellular proteins. Alternatively, they may be excreted by the cell and processed by antigen presenting cells. These antigen presenting cells can then present the drug on the surface of the cells to T cells. T cells would then produce cytokines and to stimulate B cells, and both T cell and antibody mediated responses would then occur. Glutathione usually neutralizes drugs that give rise to intermediates during metabolism. Some drugs escape neutralization. Examples of these drugs are:
  • sulfonamide antimicrobials
  • phenacetin
  • phenytoin,carbamazepine, and lamotrigine
  • procainamide
  • halothane