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Antihistamines are drugs which treat allergic rhinitis and other allergies. Typically people take antihistamines as an inexpensive, generic, over-the-counter drug that can provide relief from nasal congestion, sneezing, or hives caused by pollen, dust mites, or animal allergy with few side effects. Antihistamines are usually for short-term treatment. Chronic allergies increase the risk of health problems which antihistamines might not treat, including asthma, sinusitis, and lower respiratory tract infection. Consultation of a medical professional is recommended for those who intend to take antihistamines for longer-term use.

Although people typically use the word "antihistamine" to describe drugs for treating allergies, doctors and scientists use the term to describe a class of drug that opposes the activity of histamine receptors in the body. In this sense of the word, antihistamines are subclassified according to the histamine receptor that they act upon. The two largest classes of antihistamines are H₁-antihistamines and H₂-antihistamines.

H ₁-antihistamines work by binding to histamine H₁ receptors in mast cells, smooth muscle, and endothelium in the body as well as in the tuberomammillary nucleus in the brain. Antihistamines that target the histamine H₁-receptor are used to treat allergic reactions in the nose (e.g., itching, runny nose, and sneezing). In addition, they may be used to treat insomnia, motion sickness, or vertigo caused by problems with the inner ear. H ₂-antihistamines bind to histamine H₂ receptors in the upper gastrointestinal tract, primarily in the stomach. Antihistamines that target the histamine H₂-receptor are used to treat gastric acid conditions (e.g., peptic ulcers and acid reflux).

Histamine receptors exhibit constitutive activity, so antihistamines can function as either a neutral receptor antagonist or an inverse agonist at histamine receptors. Only a few currently marketed H ₁-antihistamines are known to function as inverse agonists.

Histamine produces increased vascular permeability, causing fluid to escape from capillaries into tissues, which leads to the classic symptoms of an allergic reaction - a runny nose and watery eyes. Histamine also promotes angiogenesis.

Antihistamines suppress the histamine-induced wheal response (swelling) and flare response (vasodilation) by blocking the binding of histamine to its receptors or reducing histamine receptor activity on nerves, vascular smooth muscle, glandular cells, endothelium, and mast cells.

Itching, sneezing, and inflammatory responses are suppressed by antihistamines that act on H1-receptors. In 2014, antihistamines such as desloratadine were found to be effective as adjuvants to standardized treatment of acne due to their anti-inflammatory properties and their ability to suppress sebum production.

H ₁-antihistamines refer to compounds that inhibit the activity of the H₁ receptor. Since the H ₁ receptor exhibits constitutive activity, H ₁-antihistamines can be either neutral receptor antagonists or inverse agonists. Normally, histamine binds to the H ₁ receptor and heightens the receptor's activity; the receptor antagonists work by binding to the receptor and blocking the activation of the receptor by histamine; by comparison, the inverse agonists bind to the receptor and both block the binding of histamine, and reduce its constitutive activity, an effect which is opposite to histamine's. Most antihistamines are inverse agonists at the H ₁ receptor, but it was previously thought that they were antagonists.

Clinically, H ₁-antihistamines are used to treat allergic reactions and mast cell-related disorders. Sedation is a common side effect of H ₁-antihistamines that readily cross the blood-brain barrier; some of these drugs, such as diphenhydramine and doxylamine, may therefore be used to treat insomnia. H ₁-antihistamines can also reduce inflammation, since the expression of NF-κB, the transcription factor the regulates inflammatory processes, is promoted by both the receptor's constitutive activity and agonist (i.e., histamine) binding at the H ₁ receptor.

A combination of these effects, and in some cases metabolic ones as well, lead to most first-generation antihistamines having analgesic-sparing (potentiating) effects on opioid analgesics and to some extent with non-opioid ones as well. The most common antihistamines utilized for this purpose include hydroxyzine, promethazine (enzyme induction especially helps with codeine and similar prodrug opioids), phenyltoloxamine, orphenadrine, and tripelennamine; some may also have intrinsic analgesic properties of their own, orphenadrine being an example.

Second-generation antihistamines cross the blood-brain barrier to a much lesser extent than the first-generation antihistamines. They minimize sedatory effects due to their focused effect on peripheral histamine receptors. However, upon high doses second-generation antihistamines will begin to act on the central nervous system and thus can induce drowsiness when ingested in higher quantity. Additionally, some second-generation antihistamines, notably cetirizine, can interact with CNS psychoactive drugs such as bupropion and benzodiazepines.

H₁ antagonists/inverse agonists

H ₂-antihistamines, like H ₁-antihistamines, exist as inverse agonists and neutral antagonists. They act on H₂ histamine receptors found mainly in the parietal cells of the gastric mucosa, which are part of the endogenous signaling pathway for gastric acid secretion. Normally, histamine acts on H ₂ to stimulate acid secretion; drugs that inhibit H ₂ signaling thus reduce the secretion of gastric acid.

H ₂-antihistamines are among first-line therapy to treat gastrointestinal conditions including peptic ulcers and gastroesophageal reflux disease. Some formulations are available over the counter. Most side effects are due to cross-reactivity with unintended receptors. Cimetidine, for example, is notorious for antagonizing androgenic testosterone and DHT receptors at high doses.

Examples include:

An H₃-antihistamine is a classification of drugs used to inhibit the action of histamine at the H₃ receptor. H ₃ receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic nerve terminals, which modulate the release of histamine. Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H ₁ receptors in the cerebral cortex. Consequently, unlike the H ₁-antihistamines which are sedating, H ₃-antihistamines have stimulant and cognition-modulating effects.

Examples of selective H ₃-antihistamines include:

H ₄-antihistamines inhibit the activity of the H₄ receptor.

Examples:

Histidine decarboxylase inhibitors

Inhibit the action of histidine decarboxylase:

Mast cell stabilizers

Mast cell stabilizers are drugs which prevent mast cell degranulation.

Currently most people who use an antihistamine to treat allergies use a second-generation drug.

The first generation of antihistamine drugs became available in the 1930s. This marked the beginning of medical treatment of nasal allergies. Research into these drugs led to the discovery that they were H1 antagonists and also to the development of H2 antagonists, where H1 antihistamines affected the nose and the H2 antihistamines affected the stomach. This history has led to contemporary research into drugs which are H3 receptor antagonist and which affect the Histamine H4 receptor.

Antihistamines can vary greatly in cost. Some patients consult their doctor about drug prices to make a decision about which antihistamine to choose. Many antihistamines are older and available in generic form. Others are newer, still under patent, and generally expensive. The newer drugs are not necessarily safer or more effective. Because so many antihistamines are available, patients can have conversations with their health care provider to choose the right drug for them.

The United States government removed two second generation antihistamines, terfenadine and astemizole, from the market based on evidence that they could cause heart problems.

Not much published research exists which compares the efficacy and safety of the various antihistamines available. The research which does exist is mostly short-term studies or studies which look at too few people to make general assumptions. Another gap in the research is in information reporting the health effects for individuals with long term allergies to take antihistamines for a long period of time. Newer antihistamines have been demonstrated to be effective in treating hives. However, there is not research comparing the relative efficacy of these drugs.

Most studies of antihistamines reported on people who are younger, so the effects on people over age 65 are not as well understood. Older people are more likely to experience drowsiness from antihistamine use than younger people. Also, most of the research has been on white people and other ethnicities are not as represented in the research. The evidence does not report how antihistamines affect women differently than men. Different studies have reported on antihistamine use in children, with various studies finding evidence that certain antihistamines could be used by children 2 years of age, and other drugs being safer for younger or older children.

1. ^ Consumer Reports (2013), Using Antihistamines to Treat Allergies, Hay Fever, & Hives - Comparing Effectiveness, Safety, and Price (PDF), Yonkers, New York: Consumer Reports, archived from the original (PDF) on 17 May 2017

2. ^ Canonica GW, Blaiss M (2011). "Antihistaminic, anti-inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: a review of the evidence". World Allergy Organ J. 4 (2): 47-53. doi:10.1097/WOX.0b013e3182093e19. PMC . PMID 23268457. The H1-receptor is a transmembrane protein belonging to the G-protein coupled receptor family. Signal transduction from the extracellular to the intracellular environment occurs as the GCPR becomes activated after binding of a specific ligand or agonist. A subunit of the G-protein subsequently dissociates and affects intracellular messaging including downstream signaling accomplished through various intermediaries such as cyclic AMP, cyclic GMP, calcium, and nuclear factor kappa B (NF-κB), a ubiquitous transcription factor thought to play an important role in immune-cell chemotaxis, proinflammatory cytokine production, expression of cell adhesion molecules, and other allergic and inflammatory conditions.1,8,12,30-32 ... For example, the H1-receptor promotes NF-κB in both a constitutive and agonist-dependent manner and all clinically available H1-antihistamines inhibit constitutive H1-receptor-mediated NF-κB production ...
Importantly, because antihistamines can theoretically behave as inverse agonists or neutral antagonists, they are more properly described as H1-antihistamines rather than H1-receptor antagonists.15

3. ^ Panula P, Chazot PL, Cowart M, et al. (2015). "International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors". Pharmacol. Rev. 67 (3): 601-55. doi:10.1124/pr.114.010249. PMC . PMID 26084539.

4. ^ Church, Diana S; Church, Martin K (15 March 2011). "Pharmacology of Antihistamines". The World Allergy Organization Journal. 4 (Suppl 3): S22-S27. doi:10.1097/1939-4551-4-S3-S22. ISSN 1939-4551. PMC . PMID 23282332.

5. ^ Fox GB, Esbenshade TA, Pan JB, Radek RJ, Krueger KM, Yao BB, Browman KE, Buckley MJ, Ballard ME, Komater VA, Miner H, Zhang M, Faghih R, Rueter LE, Bitner RS, Drescher KU, Wetter J, Marsh K, Lemaire M, Porsolt RD, Bennani YL, Sullivan JP, Cowart MD, Decker MW, Hancock AA (April 2005). "Pharmacological properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological characterization and broad preclinical efficacy in cognition and schizophrenia of a potent and selective histamine H3 receptor antagonist". The Journal of Pharmacology and Experimental Therapeutics. 313 (1): 176-90. doi:10.1124/jpet.104.078402. PMID 15608077.

6. ^ Ligneau X, Lin J, Vanni-Mercier G, Jouvet M, Muir JL, Ganellin CR, Stark H, Elz S, Schunack W, Schwartz J (November 1998). "Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist". The Journal of Pharmacology and Experimental Therapeutics. 287 (2): 658-66. PMID 9808693.

7. ^ Ostrom, NK (2014). "The history and progression of treatments for allergic rhinitis". Allergy and Asthma Proceedings. 35 Suppl 1 (3): S3-10. doi:10.2500/aap.2014.35.3758. PMID 25582156.

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Antihistamines are drugs which treat allergic rhinitis and other allergies. Typically people take antihistamines as an inexpensive, generic, over-the-counter drug that can provide relief from nasal congestion, sneezing, or hives caused by pollen, dust mites, or animal allergy with few side effects. Antihistamines are usually for short-term treatment.

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