Histamine antagonist

Histamine antagonist

A histamine antagonist (commonly called an antihistamine) is a pharmaceutical drug that inhibits the action of histamine by either blocking its attachment to histamine receptors, or inhibiting the enzymatic activity of histidine decarboxylase which catalyzes the transformation of histidine into histamine (atypical antihistaminics). Histamine antagonists are commonly used for the relief of allergies caused by intolerance of proteins.[1]

Clinical effects

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 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.[2] Antihistamines have also been used with great success in the treatment of brown recluse (genus Loxosceles) spider bites, as well as other arthropod bites that cause necrosis.[3]

Clinical: H1- and H2-receptor antagonists

H1-receptor antagonists

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.[4] 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, so are less sedating. However, high doses can still induce the central nervous system drowsiness.

H1 antagonist examples include:

H2-receptor antagonists

H2 antagonists, like H1 antagonists, are also inverse agonists and not true antagonists. They act on H2 histamine receptors found principally 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:

Experimental: H3- and H4-receptor antagonists

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

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

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. ^ Sicherer, Scott H. M.D., Understanding and Managing Your Child's Food Allergy. Baltimore: The Johns Hopkins University Press, 2006 ISBN 0-8018-8492-6.
  2. ^ Monroe, EW; Daly, AF; Shalhoub, RF (1997). "Appraisal of the validity of histmine-induced wheal and flare is used to predict the clinical efficacy of antihistamines". The Journal of allergy and clinical immunology 99 (2): S798–806.  
  3. ^ Paul K. Carlton Jr, MD, FACS The Texas A&M University Health Science Center, College Station, Tex
  4. ^ Leurs R, Church MK, Taglialatela M (2002). "H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects". Clin Exp Allergy 32 (4): 489–98.  
  5. ^ Yoneyama H, Shimoda A, Araki L, 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.  
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  7. ^ LLigneau X, Lin J, Vanni-Mercier G, Jouvet M, Muir JL, Ganellin CR, Stark H, Elz S, Schunack W, Schwartz J (November 1998). -receptor antagonist"3"Neurochemical and behavioral effects of ciproxifan, a potent histamine H. The Journal of Pharmacology and Experimental Therapeutics 287 (2): 658–66.  
  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 (1 September 2004). "Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist".  

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