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{{DISPLAYTITLE:H<sub>1</sub> antagonist}}
An '''H<sub>1</sub> antagonist''' is a [[histamine antagonist]] of the [[histamine H1 receptor|H<sub>1</sub> receptor]] that serves to reduce or eliminate effects mediated by [[histamine]], an endogenous chemical mediator released during [[allergy|allergic reactions]]. Agents where the main therapeutic effect is mediated by negative modulation of histamine receptors are termed antihistamines—other agents may have antihistaminergic action but are not true antihistamines.

In common use, the term "antihistamine" refers only to H<sub>1</sub> antagonists, also known as H<sub>1</sub>-receptor antagonists and H<sub>1</sub>-antihistamines. It has been discovered that these H<sub>1</sub>-antihistamines are actually [[inverse agonist]]s at the histamine H<sub>1</sub>-receptor, rather than [[receptor antagonist|antagonists]] ''per se''.<ref>{{Cite journal|pmid=11972592 |doi=10.1046/j.0954-7894.2002.01314.x |title=H<sub>1</sub>-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects |year=2002 |month=April |author=Leurs R, Church MK, Taglialatela M  |journal=Clinical & Experimental Allergy |volume=32 |issue=4 |pages=489–98}}</ref>

==Pharmacology==
In type I hypersensitivity allergic reactions, an [[allergen]] (a type of [[antigen]]) interacts with and cross-links surface IgE [[antibody|antibodies]] on [[mast cell]]s and [[basophil]]s. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell [[degranulation]] and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through [[histamine receptor]]s.

Histamine, acting on H<sub>1</sub>-receptors, produces [[itch|pruritus]], [[vasodilation]], [[hypotension]], [[Flushing (physiology)|flushing]], [[headache]], [[tachycardia]], [[bronchoconstriction]], increase in [[vascular permeability]], potentiation of [[pain]], and more.<ref>{{Cite journal|first=F. Estelle R. |last=Simons |title=Advances in H<sub>1</sub>-antihistamines |journal=[[The New England Journal of Medicine]] |issn=0028-4793 |volume=351 |issue=21 |pages=2203–17 |year=2004 |month=November |pmid=15548781 |doi=10.1056/NEJMra033121}}</ref>

While H<sub>1</sub>-antihistamines help against these effects, they work only if taken before contact with the allergen. In severe allergies, such as [[anaphylaxis]] or [[angioedema]], these effects may be so severe as to be life-threatening. Additional administration of [[epinephrine]], often in the form of an autoinjector ([[Epi-pen]]), is required by people with such hypersensitivities.

==Clinical use of H<sub>1</sub>-antihistamines==
===Indications===
H<sub>1</sub>-antihistamines are clinically used in the treatment of histamine-mediated allergic conditions. Specifically, these indications may include:<ref name="Rossi">Rossi S (Ed.) (2004). ''[[Australian Medicines Handbook]] 2004''. [[Adelaide]]: Australian Medicines Handbook. ISBN 0-9578521-4-2 {{Page needed|date=September 2010}}</ref>

* Allergic [[rhinitis]]
* Allergic [[conjunctivitis]]
* Allergic [[skin|dermatological]] conditions ([[contact dermatitis]])
* [[Urticaria]]
* [[Angioedema]]
* Diarrhea
* [[Pruritus]] ([[atopic dermatitis]], insect bites)
* [[Anaphylaxis|Anaphylactic]] or anaphylactoid reactions—adjunct only
* Nausea and vomiting (first-generation H<sub>1</sub>-antihistamines)
* Sedation (first-generation H<sub>1</sub>-antihistamines)

H<sub>1</sub>-antihistamines can be administered topically (through the [[skin]], [[nose]], or [[eye]]s) or systemically, based on the nature of the allergic condition.

The authors of the American College of Chest Physicians Updates on Cough Guidelines (2006) recommend that, for cough associated with the common cold, first-generation antihistamine-decongestants are more effective than newer, non-sedating antihistamines.  First-generation antihistamines include [[diphenhydramine]] (Benadryl); carbinoxamine (Clistin); clemastine (Tavist); chlorpheniramine (Chlor-Trimeton) and
brompheniramine (Dimetane). However, it is important to note that a 1955 study of "antihistaminic drugs for colds," carried out by the U.S. Army Medical Corps, reported that "there was no significant difference in the proportion of cures reported by patients receiving oral antihistaminic drugs and those receiving oral placebos. Furthermore, essentially the same proportion of patients reported no benefit from either type of treatment."<ref>{{Cite journal|pmid=15415236 |year=1950 |month=May |author=Hoagland, RJ; Deitz, EN; Myers, PW; Cosand, HC |title=Antihistaminic drugs for colds: evaluation based on a controlled study |volume=143 |issue=2 |pages=157–60 |issn=0002-9955 |journal=[[Journal of the American Medical Association]] |doi=10.1001/jama.1950.02910370007003 |doi_brokendate=4 June 2009 |url=http://jama.ama-assn.org/cgi/content/summary/143/2/157}}</ref>

===Adverse drug reactions===
[[Adverse drug reaction]]s are most commonly associated with the first-generation H<sub>1</sub>-antihistamines. This is due to their relative lack of selectivity for the H<sub>1</sub>-receptor.

The most common adverse effect is sedation; this "side-effect" is utilized in many [[over-the-counter substance|OTC]] sleeping-aid preparations. Other common adverse effects in first-generation H<sub>1</sub>-antihistamines include dizziness, [[tinnitus]], blurred vision, [[Euphoria (emotion)|euphoria]], uncoordination, [[anxiety]], [[insomnia]], tremor, [[nausea]] and vomiting, [[constipation]], [[diarrhea]], dry mouth, and dry cough. Infrequent adverse effects include urinary retention, [[palpitation]]s, [[hypotension]], [[headache]], [[hallucination]], and [[psychosis]].<ref name="Rossi" />

The newer second-generation H<sub>1</sub>-antihistamines are far more selective for peripheral histamine H<sub>1</sub>-receptors and have a far better tolerability profile compared to the first-generation agents. The most common adverse effects noted for second-generation agents include drowsiness, fatigue, headache, nausea and dry mouth.<ref name="Rossi" />

==First-generation (non-selective, classical)==
These are the oldest H<sub>1</sub>-antihistaminergic drugs and are relatively inexpensive and widely available. They are effective in the relief of allergic symptoms, but are typically moderately to highly potent muscarinic [[acetylcholine receptor]] ([[anticholinergic]]) antagonists as well. These agents also commonly have action at α-[[adrenergic receptor]]s and/or [[5-HT receptor]]s. This lack of receptor selectivity is the basis of the poor tolerability profile of some of these agents, especially compared with the second-generation H<sub>1</sub>-antihistamines. Patient response and occurrence of adverse drug reactions vary greatly between classes and between agents within classes.

===Classes===
The first H<sub>1</sub>-antihistamine discovered was [[piperoxan]], by [[:fr:Ernest Fourneau|Ernest Fourneau]] (French) and [[Daniel Bovet]] (1933) in their efforts to develop a [[guinea pig]] animal model for [[anaphylaxis]] at the [[Pasteur Institute]] in [[Paris]].<ref>{{Cite journal|first=Ernest |last=Fourneau |coauthors=[[Daniel Bovet]] |year=1933 |title=Recherches sur l'action sympathicolytique d'un nouveau derive du dioxane |journal=Archives Internationales de Pharmacodynamie et de Therapie |issn=0003-9780 |volume=46 |pages=178–91}}</ref> Bovet went on to win the 1957 [[Nobel Prize in Physiology or Medicine]] for his contribution. Following their discovery, the first-generation H<sub>1</sub>-antihistamines were developed in the following decades. They can be classified on the basis of chemical structure, and agents within these groups have similar properties.

{| class="wikitable"
| '''Class''' || '''Description''' || '''Examples'''
 |-
 | Ethylenediamines || Ethylenediamines were the first group of clinically effective H<sub>1</sub>-antihistamines developed. ||
* [[Mepyramine]] (pyrilamine)
* [[Antazoline]]
 |-
 | Ethanolamines || Diphenhydramine was the prototypical agent in this group. Significant [[anticholinergic]] adverse effects, as well as sedation, are observed in this group but the incidence of gastrointestinal adverse effects is relatively low.<ref name="Rossi" /><ref name="Nelson">{{Cite book|first=Wendel L. |last=Nelson |chapter=Antihistamines and Related Antiallergic and Antiulcer Agents |chapterurl=http://books.google.com/books?id=NHQQBMM-qMEC&pg=PA1004 |year=2007 |editors=William O. Foye, Thomas L. Lemke and David A. Williams |title=Foye's Principles of Medicinal Chemistry |location=[[Hagerstown, Maryland]] |publisher=[[Lippincott Williams & Wilkins]] |pages=1004–1027 |isbn=978-0-7817-6879-5 |oclc=149596645}}</ref> ||
* [[Diphenhydramine]]
* [[Carbinoxamine]]
* [[Doxylamine]]
* [[Clemastine]]
* [[Dimenhydrinate]]
 |-
 | Alkylamines || The [[isomer]]ism is a significant factor in the activity of the agents in this group. ''E''-triprolidine, for example, is 1000-fold more potent than ''Z''-triprolidine. This difference relates to the positioning and fit of the molecules in the histamine H<sub>1</sub>-receptor binding site.<ref name="Nelson" />  Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse effects, but relatively greater incidence of paradoxical [[central nervous system]] (CNS) stimulation.<ref name="Rossi" /> ||
* [[Pheniramine]]
* [[Chlorphenamine]] (chlorpheniramine)
* [[Dexchlorpheniramine]]
* [[Brompheniramine]]
* [[Triprolidine]]
* [[Dimetindene]]
 |-
 | Piperazines || These compounds are structurally-related to the ethylenediamines and the ethanolamines, and produce significant [[anticholinergic]] adverse effects. Compounds from this group are often used for motion sickness, vertigo, nausea, and vomiting. The second-generation H<sub>1</sub>-antihistamine [[cetirizine]] also belongs to this chemical group.<ref name="Nelson" />  ||
* [[Cyclizine]]
* [[Chlorcyclizine]]
* [[Hydroxyzine]]
* [[Meclizine]]
 |-
 | Tricyclics and Tetracyclics || These compounds differ from the [[phenothiazine]] [[antipsychotic]]s in the ring-substitution and chain characteristics.<ref name="Nelson" /> They are also structurally-related to the [[tricyclic antidepressant]]s (and [[tetracyclic antidepressant|tetracyclics]]), explaining the H<sub>1</sub>-antihistaminergic adverse effects of those three drug classes and also the poor tolerability profile of tricyclic H<sub>1</sub>-antihistamines. The second-generation H<sub>1</sub>-antihistamine loratadine was derived from compounds in this group. ||
* [[Promethazine]]
* [[Alimemazine]] (trimeprazine)
* [[Cyproheptadine]]
* [[Azatadine]]
* [[Ketotifen]]
|}

===Common structural features===
* Two aromatic rings, connected to a central carbon, nitrogen or CO
* Spacer between the central X and the amine, usually 2-3 carbons in length, linear, ring, branched, saturated or unsaturated
* Amine is substituted with small alkyl groups, e.g., CH3

[[Image:Antihistamine.svg|200px]]<br>
'''X = N, R1 = R2 = small alkyl groups'''<br>
'''X = C'''<br>
'''X = CO'''

*Chirality at X can increase both the potency and selectivity for H1-receptors
*For maximum potency, the two aromatic rings should be orientated in different planes
** for example, tricyclic ring system is slightly puckered and the two aromatic rings lie in different geometrical planes, giving the drug a very high potency.

==Second-generation and third-generation (selective, non-sedating)==
=== Second-generation ===
Second generation H<sub>1</sub>-antihistamines are newer drugs that are much more selective for peripheral H<sub>1</sub> receptors in preference to the [[central nervous system]] histaminergic and cholinergic receptors. This selectivity significantly reduces the occurrence of adverse drug reactions compared with first-generation agents, while still providing effective relief of allergic conditions.
The reason for their reduction in sedative effects is due to the fact that most of these compounds are [[zwitterionic]] at physiological pH (around pH 7.4). Being zwitterionic in nature means that the compounds are very polar and therefore will not cross the blood brain barrier and so will act mainly outside the central nervous system leaving these antihistamines with little or no sedative qualities.

Systemic:
* [[Acrivastine]]
* [[Astemizole]]
* [[Cetirizine]]
* [[Ebastine]]
* [[Bilastine]]
* [[Bepotastine]]
* [[Ketotifen]]
* [[Loratadine]]
* [[Mizolastine]]
* [[Terfenadine]]

Topical:

* [[Azelastine]]
* [[Levocabastine]]
* [[Olopatadine]]

===Third-generation===
Third-generation H<sub>1</sub>-antihistamines are the active [[enantiomer]] (levocetirizine) or [[metabolite]] (desloratadine & fexofenadine) derivatives of second-generation drugs intended to have increased [[efficacy]] with fewer [[adverse drug reaction]]s. Indeed, fexofenadine is associated with a decreased risk of [[cardiac arrhythmia]] compared to terfenadine. However, there is little evidence for any advantage of levocetirizine or desloratadine, compared to [[cetirizine]] or [[loratadine]], respectively{{Citation needed|date=November 2009}}.

There is some controversy associated with the use of this term.<ref name="pmid17136293">{{Cite journal|pmid=17136293 |doi=10.1590/S0021-75572006000700007 |year=2006 |month=November |first=Inês Cristina |last=Camelo-Nunes |title=Novos anti-histamínicos: uma visão crítica (New antihistamines: a critical view) |volume=82 |issue=5 |pages=S173–80 |issn=0021-7557 |journal=Jornal de Pediatria |language=[[Portuguese language|Portuguese]]}}</ref>

Systemic:
* [[Levocetirizine]]<ref name="pmid16445787">{{Cite journal|pmid=16445787 |doi=10.1111/j.1365-2133.2005.07049.x |year=2006 |month=March |author=Nettis, E; Colanardi, MC; Barra, L; Ferrannini, A; Vacca, A; Tursi, A |title=Levocetirizine in the treatment of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study |volume=154 |issue=3 |pages=533–8 |issn=0007-0963 |journal=The British journal of dermatology}}</ref>
* [[Desloratadine]]<ref name="pmid16109168">{{Cite journal|pmid=16109168 |pmc=1192807 |doi=10.1186/1471-2210-5-13 |year=2005 |month=August |author=Howell, G, III; West, L; Jenkins, C; Lineberry, B; Yokum, D; Rockhold, R |title=In vivo antimuscarinic actions of the third generation antihistaminergic agent, desloratadine |volume=5 |issue= |pages=13 |issn= |journal=BMC pharmacology |url=http://www.biomedcentral.com/1471-2210/5/13 |format=Free full text}}</ref>
* [[Fexofenadine]]<ref name="pmid12575922">{{Cite journal|pmid=12575922 |year=2002 |month=September |author=Vena, GA; Cassano, N; Filieri, M; Filotico, R; D'Argento, V; Coviello, C |title=Fexofenadine in chronic idiopathic urticaria: a clinical and immunohistochemical evaluation |volume=15 |issue=3 |pages=217–224 |issn=0394-6320 |journal=International Journal of Immunopathology and Pharmacology}}</ref>

==References==
{{Reflist|2}}

==External links==
* {{MeshName|Antihistaminics,+H1}}

{{Antihistamines}}
{{Histaminergics}}
{{Major Drug Groups}}
{{Neuromodulation}}
{{Use dmy dates|date=September 2010}}

{{DEFAULTSORT:H1 Antagonist}}
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