True or classic drug allergy is mediated by the drug activating the allergic protein (IgE) which in turn causes Mast cells in the skin and throughout the body to release histamine. However, it has been known for quite some time that some drug reactions are not mediated by IgE. These have been referred to as pseudo-allergic reactions or anaphylactoid (as opposed to anaphylaxis).
Then comes the discovery of Mas-related G protein – coupled receptor X2 (MRGPRX2) which sits on the surface of Mast cells (primarily Mast cells in the skin). When this receptor is stimulated it too causes Mast cells to release histamine. The most common drugs that do this are: Leupron, Firazyr, Cetrotide, neuromuscular blocking agents (used in anesthesia), opiates, fluoroquinolones and vancomycin.
The one good thing about MRGPRX2 receptor is it is “low-affinity” i.e., it requires a high concentration of drug to be activated. This is in contrast to the IgE receptor which is high affinity. A practical example is opiate. If the dose is kept low enough many people can tolerate these drugs without reaction.