The Info List - Antihistamines

--- Advertisement ---


ANTIHISTAMINES are drugs which treat allergic rhinitis and other allergies . Antihistamines
can give relief when a person has nasal congestion , sneezing , or hives because of pollen , dust mites , or animal allergy . Typically people take antihistamines as an inexpensive, generic , over-the-counter drug with few side effects. As an alternative to taking an antihistamine, people who suffer from allergies can instead avoid the substance which irritates them. 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 . Doctors recommend that people talk to them before any longer term use of antihistamines.

Although typical people 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 . 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 .

receptors exhibit constitutive activity , so antihistamines can function as either a neutral receptor antagonist or an inverse agonist at histamine receptor. Only a few currently marketed H1-antihistamines are known to function as inverse agonists.


* 1 Medical uses

* 2 Types

* 2.1 H1-antihistamines

* 2.1.1 H1 antagonists * 2.1.2 H1 inverse agonists

* 2.2 H2-antihistamines

* 3 Research

* 3.1 H3-antihistamines * 3.2 H4-antihistamines

* 4 Related agents

* 4.1 Histidine decarboxylase inhibitors * 4.2 Mast cell stabilizers

* 5 History * 6 Society and culture * 7 Research * 8 Special
populations * 9 See also * 10 References * 11 External links


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 .

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.



Main article: H1-antihistamine

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

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

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 .

H1 Antagonists

Examples of H1 antagonists include:

* Acrivastine (see _Benadryl_ entry in this section) * Azelastine * Benadryl is a brand name for different H1 antagonist anitihistamine 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 (see _Benadryl_ entry in this section) * Chlorodiphenhydramine * Chlorphenamine * Chlorpromazine (antipsychotic) * Clemastine * Cyclizine * Cyproheptadine * 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) * Hydroxyzine (Vistaril) * 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 * Tripelennamine * Triprolidine

H1 Inverse Agonists

The H1 receptor inverse agonists include:

* 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)


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


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:

* Clobenpropit , * ABT-239 * Ciproxifan , * Conessine * A-349,821 . * Thioperamide



* Thioperamide * JNJ 7777120 * VUF-6002



Inhibit the action of histidine decarboxylase :

* Tritoqualine * Catechin


Main article: Mast cell stabilizer

Mast cell stabilizers are drugs which prevent mast cell degranulation .

* cromolyn sodium * Nedocromil * β-agonists


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 let 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 .


can vary greatly in cost. Some patients consult with 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 are 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.


* Antileukotriene


* ^ _A_ _B_ _C_ _D_ _E_ _F_ _G_ _H_ _I_ _J_ _K_ _L_ _M_ _N_ _O_ _P_ _Q_ _R_ _S_ _T_ _U_ _V_ _W_ _X_ _Y_ Consumer Reports (2013), _Using Antihistamines
to Treat Allergies, Hay Fever, ">(PDF), Yonkers, New York : Consumer Reports

* ^ _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. PMC 3500039  . PMID 23268457 . doi :10.1097/WOX.0b013e3182093e19 . 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. PMC 4485016  _. PMID 26084539 . doi :10.1124/pr.114.010249 . * ^ 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. PMID 11972592 . doi :10.1046/j.0954-7894.2002.01314.x . * ^ _A_ _B_ _C_ _D_ _E_ _F_ "H1 receptor". IUPHAR/BPS Guide to Pharmacology. Retrieved 8 October 2015. * ^ Norby, K (April 1, 1995). "Evidence of a dual role of endogenous histamine in angiogenesis.". _PubMed_. Int. J. Exp. Pathol. pp. 87–92. PMID 7540412 . Missing or empty url= (help ) * ^ 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. PMID 9042073 . doi :10.1016/s0091-6749(97)70128-3 . * ^ 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. PMID 25081735 . doi :10.1111/jdv.12403 . * ^ Layton AM (2016). "Top Ten List of Clinical Pearls in the Treatment of Acne Vulgaris". _Dermatol Clin_. 34 (2): 147–57. PMID 27015774 . doi :10.1016/j.det.2015.11.008 . * ^ "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. PMID 18278935 . doi :10.1021/jo702181x . * ^ 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 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 . * ^ 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. PMID 15294456 . doi :10.1016/j.bcp.2004.05.048 . * ^ _A_ _B_ Ostrom, NK (2014). "The history and progression of treatments for allergic rhinitis.". _Allergy and asthma proceedings_. 35 Suppl 1: S3–10. PMID 25582156 . * ^ _A_ _B_ Jones, 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. PMID 27119574 .


* Histamine