Open Access Articles- Top Results for Histamine antagonist

Histamine antagonist

A histamine antagonist, commonly called an antihistamine, is a pharmaceutical drug class which, as of 2015, includes two types of drugs: histamine H1-receptor antagonists and histamine H2-receptor antagonists. Antagonists of the histamine H1-receptor are used to treat allergic reactions in the nose (e.g., itching, runny nose, and sneezing) and which are used off-label for insomnia. They are sometimes also used to treat motion sickness or vertigo caused by problems with the inner ear. Antagonists of the histamine H2-receptor are used to treat gastric acid conditions (e.g., peptic ulcers and acid reflux). They work by binding[note 1] to histamine H1 receptors in mast cells, smooth muscle, and endothelium in the body and tuberomammillary nucleus the brain or histamine H2 receptors in the upper gastrointestinal tract, primarily in the stomach.

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.[citation needed]

Antihistamines suppress the histamine-induced wheal response (swelling) and flare response (vasodilation) by blocking the binding of histamine to its receptors on nerves, vascular smooth muscle, glandular cells, endothelium, and mast cells. They exert a competitive antagonism to histamines.

Itching and sneezing are suppressed by antihistamine blocking of H1-receptors on nasal sensory nerves.[1]


H1-receptor antagonists

Main article: H1 antagonist

In common use, the term antihistamine refers only to compounds that inhibit action at the H1 receptor (and not H2, etc.).

Rather than "true" antagonists, H1-antihistamines are actually inverse agonists at the histamine H1-receptor.[2] Clinically, H1 antagonists are used to treat allergic reactions. Sedation is a common side effect, and some H1 antagonists, such as diphenhydramine and doxylamine, are also used to treat insomnia.

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 antagonist examples include:

H2-receptor antagonists

Main article: H2 antagonist

H2 antagonists, like H1 antagonists, are also inverse agonists and not true 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 block H2 signaling thus reduce the secretion of gastric acid. H2 antagonists 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-antagonists have a stimulant and nootropic effect, and are being investigated for the treatment of conditions such as ADHD, Alzheimer's disease, and schizophrenia, whereas H4-antagonists appear to have an immunomodulatory role and are being investigated as anti-inflammatory and analgesic drugs.

H3-receptor antagonists

Main article: H3 antagonist

An H3-receptor antagonist is a classification of drugs used to block the action of histamine at the H3 receptor. Unlike the H1 and H2 receptors which have primarily peripheral actions, but cause sedation if they are blocked in the brain, 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 antagonist antihistamines which are sedating, H3 antagonists have stimulant and nootropic effects, and are being researched as potential drugs for the treatment of neurodegenerative conditions such as Alzheimer's disease.

Examples of selective H3 antagonists include:

H4-receptor antagonists



Atypical antihistaminics

They inhibit the enzymatic activity of histidine decarboxylase:

Mast cell stabilizers

Main article: Mast cell stabilizer

Mast cell stabilizers appear to stabilize the mast cells to prevent degranulation and mediator release. These drugs are not usually classified as histamine antagonists, but have similar indications. Examples include:


  1. ^ Monroe EW, Daly AF, Shalhoub RF (Feb 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. PMID 9042073. doi:10.1016/s0091-6749(97)70128-3. 
  2. ^ Leurs R, Church MK, Taglialatela M (Apr 2002). "H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects". Clinical and Experimental Allergy 32 (4): 489–98. PMID 11972592. doi:10.1046/j.0954-7894.2002.01314.x. 
  3. ^ Yoneyama H et al. (Mar 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. PMID 18278935. doi:10.1021/jo702181x. 
  4. ^ Fox GB, Esbenshade TA, Pan JB, Radek RJ, Krueger KM, Yao BB et al. (Apr 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. PMID 15608077. doi:10.1124/jpet.104.078402. 
  5. ^ Ligneau X, Lin J, Vanni-Mercier G, Jouvet M, Muir JL, Ganellin CR et al. (Nov 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. 
  6. ^ Esbenshade TA, Fox GB, Krueger KM, Baranowski JL, Miller TR, Kang CH et al. (Sep 2004). "Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist". Biochemical Pharmacology 68 (5): 933–45. PMID 15294456. doi:10.1016/j.bcp.2004.05.048. 


  1. ^ "Histamine antagonists" actually act as inverse agonists at these receptors as opposed to typical receptor antagonists.

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