| Introduction

1.1 | Histamine and histamine receptor

Histamine, an important biogenic amine in the human body, is mainly found in central nervous system neurons, gastric mucosa B cells, mast cells, basophils, and other cells1. It is synthesized from L-histidine by histidine decarboxylase. Histamine exerts its biological effects as a neurotransmitter and local mediator via four histamine receptor (HR) subtypes(H1、H2、H3、H4) that belong to the superfamily of G-protein-coupled receptors (GPCRs)2, 3. HR is a very important drug target and plays an important role in human health, such as immune regulation and anaphylactic inflammation4-7. In sensitized patients, histamine is released after the activation of IgE-mediated mast cells and basophils, causing inflammation and playing an important role in the pathogenesis of allergic diseases such as urticaria, asthma, allergic rhinitis, etc7. Histamine H1 receptors are mainly distributed on the surface of vascular endothelial cells, smooth muscle cells, neurons, and immune cells in the skin and mucosa. It’s involved in the regulation of vascular dilatation, vascular permeability, blood pressure, headache, tachycardia, sleep, memory, etc8. The histamine H2 receptor is mainly distributed on the cell surface of the gastric wall, to participate in regulating gastric acid secretion, vascular permeability, blood pressure, tachycardia, bronchiectasis, airway mucus secretion reaction, and so on9. Histamine H3 receptor is mainly distributed on the surface of histaminergic neurons, work on the regulation of histamine and the neurotransmitter release like acetylcholine 10. Histamine H4 receptor is a newly discovered receptor and is mainly involved in cell differentiation, probably mediated chemotaxis of mast cells and eosinophils11, 12.

| Antihistamines and their adverse reactions

Currently, H1 and H2 antihistamines are widely used in clinical practice. Antihistamines are commonly referred to histamine H1 receptor antagonists. H1-antihistamines act as inverse agonists that interfere with the actions of histamine at H1-receptors by combining with and stabilizing the inactive conformation of H1-receptors13. H1-antihistamines also have anti-allergic effects by decreasing antigen presentation, expression of proinflammatory cytokines and cell adhesion molecules. Moreover, through transcription factor nuclear factor -KB, it inhibits mast cell activation and histamine release in a concentration-dependent manner 14-16. It is widely used in the treatment of allergic rhinitis, urticaria, and other allergic diseases. Since the successful development of the first antihistamine in 193717, antihistamines have experienced the development of the first generation, the second generation, and the second generation of improved varieties.

1.2.1 | First generation H1 antihistamines

Classic H1 receptor antagonists before the 1970s are commonly referred to the first-generation H1 antihistamines, such as chlorphenamine, diphenhydramine, promethazine, tripelennamine, and so on. First-generation H1 antihistamines are used to treat allergic reactions such as urticaria, allergic rhinitis, bronchial asthma, antipruritic, and antiemetic, etc 18. The curative effect is definite. However, because of its short half-life, it must be given many times and the dosage is larger compared with the second-generation H1 antihistamines. First-generation H1 antihistamines, also known as sedating antihistamines, penetrate well through the blood-brain barrier and bind to the histamine receptors of the central nervous system. Then it can produce inhibitory and excitatory effects on the central nervous system, manifested as hallucinations, drowsiness, decreased alertness, or restlessness, tension, insomnia, etc19. Almost all the first-generation antihistamines have a sedative effect, especially hydroxyzine, cyproheptadine, and diphenhydramine. Due to poor selectivity for H1 receptors, as well as block cholinergic receptors and serotonin activity, the incidence of dry mouth, tachycardia, gastrointestinal disorders, dementia, and other adverse reactions is high 20, 21. Therefore, in recent years, except for a few local applications or recurrent applications, most first-generation H1 antihistamines have withdrawn from the market.

| Second generation H1 antihistamines

Second-generation H1 antihistamines include loratadine, imidazoline, terfenadine, and so on. In addition to their high histamine H1 receptor selectivity, they also have other anti-allergic effects, such as antagonizing intercellular adhesion molecules (ICAM). Compared with the first-generation H1 antihistamines, Second-generation H1 antihistamines have obvious advantages. It has lower lipotropy, rarely through the blood-brain barrier, and not a competitive priority and peripheral H1 receptor 22, 23. Because of its long half-life, the dosage used is relatively small. What’s more, with low or no sedation, there are fewer side effects such as sedation, drowsiness, and dry mouth, so they are also called non-sedating antihistamines24. However, they also have some defects. The second-generation H1 antihistamines like ketotifen, cetirizine, nitrogen, and acrivastine, still have a relatively light central sedative effect. Astemizole, azelastine, and ketotifen can stimulate increased appetite and lead to increased weight, of which astemizole is the most serious. The most serious adverse reaction is cardiotoxicity especially induced by terfenadine and astemizole, followed by loratadine, Ketotifen, and cetirizine, etc25, 26. Among the adverse reactions of the cardiovascular system, arrhythmia was the most common clinical picture. Although the incidence of such adverse reactions is relatively low, the consequences are severe.

| New H1 antihistamines

In recent decades, new second-generation antihistamines27—a modified version of a second-generation antihistamine have been introduced. The new second-generation antihistamines are derived from the active metabolites or optical isomers of second-generation antihistamines, such as desloratadine, levocetirizine, and fexofenadine. It is effective and has few adverse reactions, and no serious adverse reactions have been reported so far.

H2 antihistamines

Histamine H2 receptor antagonists include cimetidine, ranitidine, and famotidine, etc 28. The H2 receptor antagonist can selectively block the H2 receptor on the cell membrane, resulting in the production of cAMP in the cell wall and the decrease of gastric acid secretion. It can also partially block the secretion of gastric acid caused by histamine, pentagastrin, cholinergic drugs, and stimulation of the vagus nerve29. Mainly used for the treatment of gastric and duodenal ulcers30,Some studies have found that histamine H2 receptor antagonist (H2RA) can also improve the symptoms of heart failure (HF) patients31, 32. Histamine H2 receptor antagonists are safe drugs with a low incidence of serious adverse reactions. For the patients who are old age, with kidney function or other diseases is easy to produce adverse reactions like common diarrhea, headache, lethargy, fatigue, myalgia, constipation, and so on33, 34.