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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.