Histamine is a biogenic amine involved in local immune responses, regulation of gut function and neurotransmission. It exerts its actions by binding to one of four human histamine receptors (HRHs). They belong to the family of rhodopsin-like G-protein-coupled receptors (Panula et al. 2015). Histamine binding to HRHs brings about many physiologic changes, including neurotransmission, inflammation, smooth muscle contraction, dilatation of capillaries, chemotaxis, cytokine production and gastric acid secretion. The histamine H1 receptor (HRH1) is found on smooth muscle and the vascular endothelium, and in the heart and the CNS. Histamine released from neurons binds to HRH1 and causes systemic vasodilation and increased endothelial cell permeability. HRH1 displays constitutive receptor activation in the absence of agonists (Bakker et al. 2000).

More than 40 HRH1 antihistamines are available worldwide, comprising the largest class of medications used in the treatment of allergic diseases. For more than 50 years these drugs were thought to act as antagonists of HRH1 but it is now known that most of these drugs act as inverse agonists that combine with and stabilize the inactive conformation of HRH1, shifting the equilibrium toward the inactive state (Bakker et al. 2000, Nijmeijer et al. 2010). HRH1 antihistamines are functionally classified as first (old) generation and second (new) generation. First (old)–generation HRH1 antihistamines may cross the blood-brain barrier and interfere with neurotransmission in the CNS, with adverse affects, even resulting in death in overdose cases. First-generation HRH1 antihistamines include chlorpheniramine, diphenhydramine and hydroxyzine, amongst others. Second (new)–generation HRH1 antihistamines are used to treat allergic rhinitis, allergic conjunctivitis, and urticaria. These drugs minimally cross the blood-brain barrier and do not impair alertness, learning, memory, or multitasking and are minimally sedative. Overdose does not cause toxicity or death. Second-generation HRH1 antihistamines include bilastine, ceterizine, fexofenadine, loratadine and reupatadine, amongst others (Yanai et al. 2012, Simons & Akdis 2014, Fein et al. 2019).