The Effect of Antihistamines on Asthmatics

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We are now Celebrating a century of progress after the initial discovery of histamine’s physiological and pathological roles ,and 70 years after the initial introduction of H1-antihistamines for medical use[1]. this review will discuss histamine role in allergic reaction such as asthma and chronic pruritus , mechanisms of action of antihistamines ,types of histamine receptor ,classes of antihistamines , Role of Antihistamines in allergic inflammation, side effects, and Clinical Trials Targeting Histamine Receptors , Numerous cell types associated with inflammation have been shown to modulate the activity by H4R in vivo, so H4R is used as a novel drug target for allergy and inflammation treatment . Clinical trials models indicate that H4 R could account for many other histamine roles which are not blocked by the H1 receptor . In particular, The discovery and expression of the H4R on various immune and inflammatory cells has initiated a re-evaluation of histamine action , suggesting a new overlapping between H1 and H4 function [2]. Antihistamines have a long and rich history and a very promising future.

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On the off chance that you’ve got an sensitivity, chances are you’ve listened of is a biologically active substance produced by the body to potentiate the inflammatory and immune responses and to maintain homeostasis. Histamine receptors are hydrophobic and located in different parts of the body that bind with histamine to deliver a particular impact on the living being . There are 4 identified receptors, called H1-H4. The receptor that the histamine responds with is dependant upon where the histamine is released within the body. Histamine has assorted impacts, both pro-inflammatory and anti-inflammatory, that are decided by both the histamine receptor subtype and the stimulated types of cells.H1R are found in numerous cells and participate in hypersensitivity reactions of type 1,while H2 receptor modifies the secretion of gastric acid and production of mucus .The H3R are found throughout the nervous system and regulate neuro-inflammatory diseases , By releasing multiple inflammatory mediators, H4R-mediated mast cell activation can control an effective inflammatory cascade; which can promote the migration of various inflammatory cells into the site of inflammation. [3]

Histamine level elevated inside the tissue causes activation of histamine receptors which leads to the development of symptoms such asbronchoconstriction and acute rhinitis.[4]

Brief history about antihistamines : in 1937, Etienne Fourneau synthesized the first antihistamine but it was toxic . Bernard N. Halpem synthesized phenbenzamine the first used antihistamine in 1942. [5]

The H1-Receptor:

The H1-receptor histamine could be a part of the superfamily of G-protein-coupled receptors (GPCRs) . H1R is present in several areas and cells involving, dendritic cells, nerves, endothelial cells, respiratory epithelial cells, and lymphocytes. Histamine activates H1R via G?q/11 then activates phospholipase C and increases Ca++ levels intracellular .As a result, histamine triggers contraction of smooth muscle in the respiratory tract, and promotes the development of platelet activating factor by activating H1R. The importance of H1R stimulation in asthma can therefore be confirmed by studies that suggest that use of H1R-antagonists could help decrease asthma symptoms and enhance lung function in severe asthma. Histamine H1 receptors are therefore found in the skin tissue and keratinocytes, and histamine raises the production of NGF in human keratinocytes via H1R .In this way, nearly all immediate hypersensitivity reactions, counting indications watched within the skin including pruritus, edema , and erythema could be triggered by H1R activation.

The H2-Receptor:

H2R is a G?s-coupled receptor , H2 Receptor is widely presented in types of cells and tissues, such a smooth muscles , B cells, T cells, cardiac tissues , dendritic cells, gastrointestinal-parietal cells, and brain . Receptor activation could stimulate the production of mucus, , and stomach acid secretion .the H2R is greatly responsible for relaxing the respiratory tract, smooth muscle cells in the blood vessels, and uterus. also, the H2Receptor helps in triggering of the Immune system, others such as antibody synthesis , reduction of basophilic degranulation, and T-cell proliferation [3]

The H3-Receptor:

H3R is G?i coupled receptor,it found in regulates levels of energy H3R insufficient mice appear changed behavior and motion, and show a metabolic disorder characterized by hyperphagia , overweight ,and elevated levels of leptin and insulin.[3]

The H4-Receptor:

H4R is G?/I coupled receptor. It is found in various cells including synovial tissue, spleen, central nervous system , sensory nerves, gastrointestinal epithelia, heart, cancer cells , and nervous system. [3]

H1-antihistamines including azatadine, cetirizine, and mizolastine are used for the treatment of activated diseases in mast cell. H2 antihistamines such as Cimetidine, ranitidine, famotidine and nizatidine are selective H2R antihistamines which decrease the secretion of gastric acid. . H3R antihistamines such as thioperamide, clobenpropit, BF2. 649, PF-03654746, JNJ-17216498, and MK 0249.H4R antihistamine including JNJ 7777120 that is commonly used for inflammation and pruritus. [3]

Mechanism of Action:

Histamine causes an increased level of vascular permeability, leading to the flow of fluid from capillaries to surrounding tissues. The end effect of that is increased vessel swelling and dilation. Antihistamines avoid this effect by acting at the H-1 receptors as antagonists.. First-generation antihistamines antagonize H-1 receptors and can cross the blood-brain barrier (BBB) into the nervous system, resulting in a distinct therapeutic and side effect compared to 2st generation antihistamines, which only bind to the peripheral histamine receptors. Side effects: dry mouth- dizziness and tinnitus and at high doses euphoria . Antihistamines Contraindicated with Hypertension, urinary retention, cardiovascular disease. [7]

SAR of H1 Antihistamines:

The two aryl moieties are very important for for effective receptor interaction, substituents in one of the aryl moieties increase potency.The nature of atom X categorize the different classes of H1 antagonists[8,9] first generation H-1 Antihistamines (classical antihistamines ); The first and second generation anthistamines are generally considerably more lipophilic than H 2 antagonist . The difference in lipophilicity arises mainly because of the substituted amino moieties, and the two aryl rings. They are rapidly absorbed and metabolized. Because of their lipophilicity, they cross the blood-brain barrier and easily bind to the cerebral H1 receptor.[9,10] first generation antihistamines.

Ethanediamines (Diphenhydramine is the prototype and the first clinically useful member of the ethanolamine group). [8] , Several therapeutically important diphenhydramine derivatives have been developed by para-methyl substitution. Due to the reduced side effects, these derivatives are stated to have higher therapeutic profiles compared to diphenhydramine. Bromodiphenhydramine, for example, is more lipid-soluble, and is twice as effective as antihistamine. [9]

Ethylenediamines: Phenbenzamine is the prototype of this class and the first useful member .Replacing the phenyl moiety of phenbenzamine with a 2-pyridyl form produced tripelennamine, which is considerably more effective . Substitution of a para-methoxy (pyrilamine or mepyramine), chloro (chloropyramine) or bromo (bromtripelennamine) may increase the activity. Replacing of the benzyl group of tripelennamine with a 2-thienylmethyl group give methapyrilene,and replacing of tripelennamine’s 2-pyridyl group with a pyrimidinyl moiety give thonzylamine both are potent H1R antagonists [9]

Propylamines : this class rank among the most active H1 antagonists. Members of this class also produce less sedation effect and have little antiemetic action. This class differ just in the para-position phenyl substituent, H (pheniramine), Br (brompheniramine)and Cl (chlorpheniramine). Halogenated pheniramines are considerably more potent 20-50 times and have a longer duration of action. [9]

Piperazines: is mainly used in the treatment of motion sickness and prophylaxis. Chlorcyclizine is used for urticaria, hay fever, symptomatic relief.[9]

Famotidine: metabolized by cytochrome P450, and has limited inhibitory effects on other drug metabolism, which lead to cause less drug-drug interactions. [12]


Antihistamines are commonly used in many allergic disorders, the new generations of H1 antagonists are more save and have fewer side effect . The therapeutic efficacy of H1R and H2R antagonists is relatively small in many inflammatory disorders. As such strong hopes are set on new ligands of histamine H3 and H4 receptors. H4R antagonists showed safety and high efficacy in animal models and several clinical trial, The function of these receptors is not yet fully understood but our understanding of their roles has increased over the past few years. [4]

Future Prospective:

There is a The functional similarity between H1R and H4R tends to open up the possibility of using synergistic therapeutic approaches so, Combination treatments using both H4R and H1R antagonists may help in the treatment of various allergic and inflammatory conditions.[3]


[1] Simons, F. Estelle R., and Keith J. Simons. ‘Histamine and H1-antihistamines: celebrating a century of progress.’ Journal of Allergy and Clinical Immunology 128.6 (2011): 1139-1150.

[2] Thurmond, Robin L., Erwin W. Gelfand, and Paul J. Dunford. ‘The role of histamine H 1 and H 4 receptors in allergic inflammation: the search for new antihistamines.’ Nature Reviews Drug Discovery 7.1 (2008): 41-53.

[3] Thangam, Elden Berla, et al. ‘The role of histamine and histamine receptors in mast cell-mediated allergy and inflammation: the hunt for new therapeutic targets.’ Frontiers in immunology 9 (2018): 1873.

[4] Tatarkiewicz, Jan, et al. ‘New antihistamines–perspectives in the treatment of some allergic and inflammatory disorders.’ Archives of medical science: AMS 15.2 (2019): 537.


[6] Church, Martin K., and Diana S. Church. ‘Pharmacology of antihistamines.’ Indian journal of dermatology 58.3 (2013): 219.

[7] Farzam, Khashayar, and Maria C. O’Rourke. ‘Antihistamines.’ StatPearls [Internet]. StatPearls Publishing, 2019

[8]Deliverd teaching materials by the department (lecture Antiallergic And Antiulcer Drugs) by: Dr; Wesam E. Mehanna

[9] DeRuiter, Jack. ‘Histamine H1-receptor antagonists: antihistaminic agents.’ Principles of Drug Action 2 (2001): 1-20

[10] Criado, Paulo Ricardo, et al. ‘Histamina, receptores de histamina e anti-histamínicos: novos conceitos.’ Anais brasileiros de dermatologia 85.2 (2010): 195-210

[11] pharmafactz,

[12] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Histamine Type-2 Receptor Antagonists (H2 Blockers) [Updated 2018 Jan 25].

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The Effect of Antihistamines on Asthmatics. (2022, Oct 05). Retrieved November 30, 2022 , from

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