a drug that neutralizes or counteracts the effects of another drug
a muscle that relaxes while another contracts; "when bending the elbow the triceps are the antagonist"
amine formed from histidine that stimulates gastric secretions and dilates blood vessels; released by the human immune system during allergic reactions
Antihistamines are drugs which treat allergic rhinitis and other allergies.[1] Antihistamines can give relief when a person has nasal congestion, sneezing, or hives because of pollen, dust mites, or animal allergy.[1] Typically people take antihistamines as an inexpensive, generic, over-the-counter drug with few side effects.[1] As an alternative to taking an antihistamine, people who suffer from allergies can instead avoid the substance which irritates them. However, this is not always possible as some substances, such as pollen, are carried in the air, thus making allergic reactions caused by them generally unavoidable.[1] Antihistamines are usually for short-term treatment.[1] Chronic allergies increase the risk of health problems which antihistamines might not treat, including asthma, sinusitis, and lower respiratory tract infection.[1] Doctors recommend that people talk to them before any longer term use of antihistamines.[1]
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.[2] 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. Antihistamines that target the histamine H1-receptor are used to treat allergic reactions in the nose (e.g., itching, runny nose, and sneezing) as well as for insomnia. They are sometimes also used to treat motion sickness or vertigo caused by problems with the inner ear. Antihistamines that target the histamine H2-receptor are used to treat gastric acid conditions (e.g., peptic ulcers and acid reflux). H1-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; H2-antihistamines bind to histamine H2 receptors in the upper gastrointestinal tract, primarily in the stomach.
Histamine receptors exhibit constitutive activity, so antihistamines can function as either a neutral receptor antagonist or an inverse agonist at histamine receptors.[2][3][4][5] Only a few currently marketed H1-antihistamines are known to function as inverse agonists.[2][5]
Contents
1Medical uses
2Types
2.1H1-antihistamines
2.1.1H1 antagonists
2.1.2H1 inverse agonists
2.2H2-antihistamines
3Research
3.1H3-antihistamines
3.2H4-antihistamines
4Related agents
4.1Histidine decarboxylase inhibitors
4.2Mast cell stabilizers
5History
6Society and culture
7Research
8Special populations
9See also
10References
11External links
Medical uses
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.[6]
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.[2][7] 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.[8][9]
Types
H1-antihistamines
Main article: H1-antihistamine
H1-antihistamines refer to compounds that inhibit the activity of the H1 receptor.[4][5] Since the H1 receptor exhibits constitutive activity, H1-antihistamines can be either neutral receptor antagonists or inverse agonists.[4][5] Normally, histamine binds to the H1 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 reduce its activity, an effect which is opposite to histamine's.[4]
The vast majority of marketed H1-antihistamines are receptor antagonists and only a minority of marketed compounds are inverse agonists at the receptor.[2][5] Clinically, H1-antihistamines are used to treat allergic reactions and mast cell-related disorders. Sedation is a common side effect of H1-antihistamines that readily cross the blood–brain barrier; some of these drugs, such as diphenhydramine and doxylamine, are therefore used to treat insomnia. H1-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 H1 receptor.[2]
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 commonly used for the 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 lower degree than the first-generation antihistamines. Their main benefit is they primarily affect peripheral histamine receptors and therefore are less sedating. However, high doses can still induce drowsiness through acting on the central nervous system. Some second-generation antihistamines, notably cetirizine, can interact with CNS psychoactive drugs such as bupropion and benzodiazepines.[10]
H1 antagonists
Examples of H1 antagonists include:
Acrivastine (see Benadryl entry in this section)
Azelastine
Benadryl is a brand name for different H1 antagonist antihistamine preparations in different regions: acrivastine is the active component of Benadryl Allergy Relief and cetirizine of Benadryl One a Day Relief in the UK; Benadryl is diphenhydramine in the US and Canada (see http://www.benadryl.ca/adult-allergy-medicine/benadryl-caplets).
Bilastine
Bromodiphenhydramine
Brompheniramine
Buclizine
Carbinoxamine
Cetirizine (Zyrtec)
Chlorodiphenhydramine
Chlorpheniramine
Clemastine
Cyclizine
Cyproheptadine
Desloratadine (Aerius)
Dexbrompheniramine
Dexchlorpheniramine
Dimenhydrinate (most commonly used as an antiemetic)
Dimetindene
Diphenhydramine (see Benadryl entry in this section)
Doxylamine (most commonly used as an over-the-counter drug sedative)
Ebastine
Embramine
Fexofenadine (Allegra/Telfast)
Hydroxyzine (Vistaril)
Levocabastine
Levocetirizine (Xyzal)
Loratadine (Claritin)
Meclizine (most commonly used as an antiemetic)
Mirtazapine (primarily used to treat depression, also has antiemetic and appetite-stimulating effects)
Olopatadine (used locally)
Orphenadrine (a close relative of diphenhydramine used mainly as a skeletal muscle relaxant and anti-Parkinsons agent)
Phenindamine
Pheniramine
Phenyltoloxamine
Promethazine
Quetiapine (antipsychotic; trade name Seroquel)
Rupatadine (Alergoliber)
Tripelennamine
Triprolidine
H1 inverse agonists
The H1 receptor inverse agonists include:[2][5]
Cetirizine (does not cross the blood–brain barrier)
Levocetirizine
Desloratadine (does not cross the blood–brain barrier)
Pyrilamine (crosses the blood–brain barrier; produces drowsiness)
H2-antihistamines
Main article: H2-antihistamine
H2-antihistamines, like H1-antihistamines, occur 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 H2 to stimulate acid secretion; drugs that inhibit H2 signaling thus reduce the secretion of gastric acid.
H2-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:
Cimetidine
Famotidine
Lafutidine
Nizatidine
Ranitidine
Roxatidine
Tiotidine
Research
These are experimental agents and do not yet have a defined clinical use, although a number of drugs are currently[when?] in human trials. H3-antihistamines have a stimulant and nootropic effect, whereas H4-antihistamines appear to have an immunomodulatory role.
H3-antihistamines
Main article: H3-antihistamine
An H3-antihistamine is a classification of drugs used to inhibit the action of histamine at the H3 receptor. H3 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 H1 receptors in the cerebral cortex. Consequently, unlike the H1-antihistamines which are sedating, H3-antihistamines have stimulant and cognition-modulating effects.
Examples of selective H3-antihistamines include:
Clobenpropit,[11]
ABT-239[12]
Ciproxifan,[13]
Conessine
A-349,821.[14]
Thioperamide
H4-antihistamines
H4-antihistamines inhibit the activity of the H4 receptor.
Examples:
Thioperamide
JNJ 7777120
VUF-6002
Related agents
Histidine decarboxylase inhibitors
Inhibit the action of histidine decarboxylase:
Tritoqualine
Catechin
Mast cell stabilizers
Main article: Mast cell stabilizer
Mast cell stabilizers are drugs which prevent mast cell degranulation.
cromolyn sodium
Nedocromil
β-agonists
History
Currently most people who use an antihistamine to treat allergies use a second generation drug.[1]
The first generation of antihistamine drugs became available in the 1930s.[15] This marked the beginning of medical treatment of nasal allergies.[15] 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.[16] This history has led to contemporary research into drugs which are H3 receptor antagonist and which affect the Histamine H4 receptor.[16]
Society and culture
Antihistamines can vary greatly in cost.[1] Some patients consult with their doctor about drug prices to make a decision about which antihistamine to choose.[1] Many antihistamines are older and available in generic form.[1] Others are newer, still under patent, and generally expensive.[1] The newer drugs are not necessarily safer or more effective.[1] Because so many antihistamines are available, patients can have conversations with their health care provider to choose the right drug for them.[1]
The United States government removed two second generation antihistamines, terfenadine and astemizole, from the market based on evidence that they could cause heart problems.[1]
Research
Not much published research exists which compares the efficacy and safety of the various antihistamines available.[1] The research which does exist are mostly short term studies or studies which look at too few people to make general assumptions.[1] 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.[1] Newer antihistamines have been demonstrated to be effective in treating hives.[1] However, there is not research comparing the relative efficacy of these drugs.[1]
Special populations
Most studies of antihistamines reported on people who are younger, so the effects on people over age 65 are not as well understood.[1] Older people are more likely to experience drowsiness from antihistamine use than younger people.[1] Also, most of the research has been on white people and other ethnicities are not as represented in the research.[1] The evidence does not report how antihistamines affect women differently than men.[1] 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]
See also
Antileukotriene
Immunotherapy
References
^ abcdefghijklmnopqrstuvwxyConsumer Reports (2013), Using Antihistamines to Treat Allergies, Hay Fever, & Hives - Comparing Effectiveness, Safety, and Price(PDF), Yonkers, New York: Consumer Reports[dead link]
^ abcdefgCanonica 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 3500039. 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
^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 4485016. PMID 26084539.
^ abcdLeurs R, Church MK, Taglialatela M (April 2002). "H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects". Clinical and Experimental Allergy. 32 (4): 489–98. doi:10.1046/j.0954-7894.2002.01314.x. PMID 11972592.
^ abcdef"H1 receptor". IUPHAR/BPS Guide to Pharmacology. Retrieved 8 October 2015.
^Norrby K (1995). "Evidence of a dual role of endogenous histamine in angiogenesis". Int J Exp Pathol. 76 (2): 87–92. PMC 1997159. PMID 7540412.
^Monroe EW, Daly AF, Shalhoub RF (February 1997). "Appraisal of the validity of histamine-induced wheal and flare to predict the clinical efficacy of antihistamines". The Journal of Allergy and Clinical Immunology. 99 (2): S798–806. doi:10.1016/s0091-6749(97)70128-3. PMID 9042073.
^Lee HE, Chang IK, Lee Y, Kim CD, Seo YJ, Lee JH, Im M (2014). "Effect of antihistamine as an adjuvant treatment of isotretinoin in acne: a randomized, controlled comparative study". J Eur Acad Dermatol Venereol. 28 (12): 1654–60. doi:10.1111/jdv.12403. PMID 25081735.
^Layton AM (2016). "Top Ten List of Clinical Pearls in the Treatment of Acne Vulgaris". Dermatol Clin. 34 (2): 147–57. doi:10.1016/j.det.2015.11.008. PMID 27015774.
^"Drug Interaction Report". drugs.com. Retrieved 28 January 2017.
^Yoneyama H, et al. (March 2008). "Efficient approaches to S-alkyl-N-alkylisothioureas: syntheses of histamine H3 antagonist clobenpropit and its analogues". The Journal of Organic Chemistry. 73 (6): 2096–104. doi:10.1021/jo702181x. PMID 18278935.
^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.
^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.
^Esbenshade TA, Fox GB, Krueger KM, Baranowski JL, Miller TR, Kang CH, Denny LI, Witte DG, Yao BB, Pan JB, Faghih R, Bennani YL, Williams M, Hancock AA (September 2004). "Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist". Biochemical Pharmacology. 68 (5): 933–45. doi:10.1016/j.bcp.2004.05.048. PMID 15294456.
^ abOstrom, 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.
^ abJones, AW (January 2016). "Perspectives in Drug Development and Clinical Pharmacology: The Discovery of Histamine H1 and H2 Antagonists". Clinical pharmacology in drug development. 5 (1): 5–12. doi:10.1002/cpdd.236. PMID 27119574.
External links
Histamine+antagonist at the US National Library of Medicine Medical Subject Headings (MeSH)
The critical role of mast cell-derived hypoxia-inducible factor-1α in human and mice melanoma growth.
Jeong HJ, Oh HA, Nam SY, Han NR, Kim YS, Kim JH, Lee SJ, Kim MH, Moon PD, Kim HM, Oh HA.SourceBiochip Research Center, Hoseo University, 165, Sechul-ri, Baebang-myun, Asan, Chungnam 336-795, Republic of Korea.
International journal of cancer. Journal international du cancer.Int J Cancer.2013 Jun 1;132(11):2492-501. doi: 10.1002/ijc.27937. Epub 2012 Dec 3.
Mast cells play an important role in tumorigenesis. Histamine released from mast cells stimulates new vessel formation by acting through the histamine1 (H1) receptor. Despite the evidence of the role of mast cells in tumor growth and angiogenesis, the potential mechanism remains to be elucidated. Th
A novel series of histamine H4 receptor antagonists based on the pyrido[3,2-d]pyrimidine scaffold: Comparison of hERG binding and target residence time with PF-3893787.
Andaloussi M, Lim HD, van der Meer T, Sijm M, Poulie CB, de Esch IJ, Leurs R, Smits RA.SourceGriffin Discoveries BV, Department of Medicinal Chemistry, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Bioorganic & medicinal chemistry letters.Bioorg Med Chem Lett.2013 May 1;23(9):2663-70. doi: 10.1016/j.bmcl.2013.02.091. Epub 2013 Mar 1.
In this work we describe the optimization of a lead compound based on the quinazoline template to give a new series of potent pyrido[3,2-d]pyrimidines as histamine H4 receptor antagonists. The pyrido[3,2-d]pyrimidine ligands have significantly reduced hERG binding compared to clinical stage compound
Novel and highly potent histamine H3 receptor ligands. Part 3: An alcohol function to improve the pharmacokinetic profile.
Labeeuw O, Levoin N, Poupardin-Olivier O, Calmels T, Ligneau X, Berrebi-Bertrand I, Robert P, Lecomte JM, Schwartz JC, Capet M.SourceBioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint-Grégoire, France. Electronic address: o.labeeuw@bioprojet.com.
Bioorganic & medicinal chemistry letters.Bioorg Med Chem Lett.2013 May 1;23(9):2548-54. doi: 10.1016/j.bmcl.2013.02.118. Epub 2013 Mar 14.
Synthesis and biological evaluation of potent histamine H3 receptor antagonists incorporating a hydroxyl function are described. Compounds in this series exhibited nanomolar binding affinities for human receptor, illustrating a new possible component for the H3 pharmacophore. As demonstrated with co
Chemical Entities of Biological Interest (ChEBI) is a freely available dictionary of molecular entities focused on 'small' chemical compounds. ... ChEBI Name histamine antagonist ChEBI ID CHEBI:37956 Definition Histamine ...
Pdf Ebooks PDF Word Power Point Ebook Histamine antagonist Histamine H2 Antagonist Drug Class Review Book 6.39 MB | Ebook Pages: 80 histamine H2-receptor antagonists in the treatment heartburn/GERD, erosive ...