From Wikipedia, the free encyclopedia
  (Redirected from Antihistamines)
Jump to: navigation, search
Drug class
Histamine structure diagram
Histamine structure
Class identifiers
ATC code R06
Mechanism of action  • Receptor antagonist
 • Inverse agonist
Biological target Histamine receptors
 • HRH1
 • HRH2
 • HRH3
 • HRH4
External links
MeSH D006633

An antihistamine is a type of pharmaceutical drug that opposes the activity of histamine receptors in the body.[1] 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 receptor.[1][2][3] Only a few currently marketed H1-antihistamines are known to function as inverse agonists.[1][3]

Medical uses[edit]

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.[citation needed]

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.[1][4]



Main article: H1 antihistamines

H1-antihistamines refer to compounds that inhibit the activity of the H1 receptor.[2][3] Since the H1 receptor exhibits constitutive activity, H1-antihistamines can be either neutral receptor antagonists or inverse agonists.[2][3] 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.[2]

The vast majority of marketed H1-antihistamines are receptor antagonists and only a minority of marketed compounds are inverse agonists at the receptor.[1][3] 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.[1]

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 the central nervous system drowsiness.

H1 antagonists[edit]

Examples of H1 antagonists include:

H1 inverse agonists[edit]

The H1 receptor inverse agonists include:[1][3]


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:


These are experimental agents and do not yet have a defined clinical use, although a number of drugs are currently in human trials. H3-antihistamines have a stimulant and nootropic effect, whereas H4-antihistamines appear to have an immunomodulatory role.


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:



Related agents[edit]

Histidine decarboxylase inhibitors[edit]

Inhibit the action of histidine decarboxylase:

Mast cell stabilizers[edit]

Main article: Mast cell stabilizer

Mast cell stabilizers are drugs which prevent mast cell degranulation.

See also[edit]


  1. ^ a b c d e f g 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 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
  2. ^ a b c d Leurs 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. 
  3. ^ a b c d e f "H1 receptor". IUPHAR/BPS Guide to Pharmacology. Retrieved 8 October 2015. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 

External links[edit]