Abstract
Many adverse reactions to therapeutic drugs appear to be allergic in nature, and are thought to be triggered by patient-specific Immunoglobulin E (IgE) antibodies that recognize the drug molecules and form complexes with them that activate mast cells. However, in recent years another mechanism has been proposed, in which some drugs closely associated with allergic-type events can bypass the antibody-mediated pathway and trigger mast cell degranulation directly by activating a mast cell-specific receptor called Mas-related G protein-coupled receptor X2 (MRGPRX2). This would result in symptoms similar to IgE-mediated events, but would not require immune priming. This review will cover the frequency, severity, and dose-responsiveness of allergic-type events for several drugs shown to have MRGPRX2 agonist activity. Surprisingly, the analysis shows that mild-to-moderate events are far more common than currently appreciated. A comparison with plasma drug levels suggests that MRGPRX2 mediates many of these mild-to-moderate events. For some of these drugs, then, MRGPRX2 activation may be considered a regular and predictable feature after administration of high doses.
Highlights
Acute adverse reactions to therapeutic drugs are those which occur within minutes to hours of drug exposure, and many of these present clinically as allergic episodes [1, 2]
Immunoglobulin E (IgE)-mediated mast cell activation should be suspected when events occur at low drug concentrations, when the events are of long duration, or when drug-specific IgE titers are high
Mivacurium injection is associated with elevated plasma histamine levels, flushing/erythema, and drops in mean arterial pressure (MAP) of greater than 20%, which all correlate with the speed of injection and drug dose
Summary
Acute adverse reactions to therapeutic drugs are those which occur within minutes to hours of drug exposure, and many of these present clinically as allergic episodes [1, 2]. The most extreme of these reactions are classified as “anaphylaxis” and can be life-threatening; these include more severe hypotension, bronchospasm, and tissue swelling, and even collapse of the cardiovascular system [3, 4] Most of these are assumed to be driven by activation of mast cells by drug-specific Immunoglobulin E (IgE) antibodies, which are called Type I immediate hypersensitivity reactions [1, 2, 5]. When a drug recognized by the antibodies is administered, it (or the conjugate) binds to multiple antibodies at the same time This brings the IgE receptors associated with the antibodies into prolonged close contact, triggering activation of the receptors and the release of mediators like histamine that generate the allergic responses [6]. Two specific issues are addressed for each drug: 1.) whether the mild-to-moderate events truly are mast cell-mediated; and 2.) whether
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