View source for H1 antagonist

{{Short description|Drugs that block the action of histamine}}
{{DISPLAYTITLE:H<sub>1</sub> antagonist}}
{{Use dmy dates|date=March 2024}}

'''H<sub>1</sub> antagonists''', also called '''H<sub>1</sub> blockers''', are a class of [[pharmaceutical drug|medications]] that block the action of [[histamine]] at the [[histamine H1 receptor|H<sub>1</sub> receptor]], helping to relieve [[allergy|allergic reactions]]. Agents where the main therapeutic effect is mediated by negative modulation of histamine receptors are termed [[antihistamine]]s; other agents may have antihistaminergic action but are not true antihistamines.{{Citation needed|date=January 2018}}

In common use, the term "antihistamine" refers only to H<sub>1</sub>-antihistamines. Virtually all H<sub>1</sub>-antihistamines function as [[inverse agonist]]s at the histamine H<sub>1</sub>-receptor, as opposed to neutral [[Receptor antagonist|antagonists]], as was previously believed.<ref name=":0">{{cite journal | vauthors = Leurs R, Church MK, Taglialatela M | title = H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects | journal = Clinical and Experimental Allergy | volume = 32 | issue = 4 | pages = 489–98 | date = April 2002 | pmid = 11972592 | doi = 10.1046/j.0954-7894.2002.01314.x | s2cid = 11849647 }}</ref><ref name=":1" /><ref>{{cite journal | vauthors = Khilnani G, Khilnani AK | title = Inverse agonism and its therapeutic significance | journal = Indian Journal of Pharmacology | volume = 43 | issue = 5 | pages = 492–501 | date = September 2011 | pmid = 22021988 | pmc = 3195115 | doi = 10.4103/0253-7613.84947 | doi-access = free }}</ref>

==Medical uses==
H<sub>1</sub>-antihistamines are used clinically to treat histamine-mediated allergic conditions. 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]])
* [[Rhinorrhea]] (runny nose)
* [[Urticaria]]
* [[Angioedema]]
* Diarrhea
* [[Pruritus]] ([[atopic dermatitis]], insect bites)
* [[Anaphylaxis|Anaphylactic]] or anaphylactoid reactions—adjunct only

First-generation H<sub>1</sub>-antihistamines can act on the central nervous system. As a result, they are also used for:<ref name="Stat2019">{{cite book |last1=Takov |first1=V |last2=Tadi |first2=P |title=Motion Sickness (in StatPearls) |date=January 2019 |pmid=30969528}}</ref>
* Nausea, vomiting, and [[motion sickness]]
* Sedation

H<sub>1</sub>-antihistamines can be administered topically (through the [[human skin|skin]], [[human nose|nose]], or [[Human eye|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, 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 | vauthors = Hoagland RJ, Deitz EN, Myers PW, Cosand HC | title = Antihistaminic drugs for colds; evaluation based on a controlled study | journal = Journal of the American Medical Association | volume = 143 | issue = 2 | pages = 157–60 | date = May 1950 | pmid = 15415236 | doi = 10.1001/jama.1950.02910370007003 }}</ref>

=={{Anchor|Adverse drug reactions}} Side effects==
<!--linked here from Hypnotic-->
[[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 and their ability to cross the [[blood–brain barrier]].

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]], incoordination, [[anxiety]], increased appetite leading to [[weight gain]], [[insomnia]], tremor, [[nausea]] and vomiting, [[constipation]], [[diarrhea]], dry mouth, and dry cough. Infrequent adverse effects include urinary retention, [[palpitation]]s, [[hypotension]], [[headache]], [[hallucination]], [[psychosis]] and [[erectile dysfunction]].<ref name="Rossi" /><ref>{{cite web | url=https://www.yahoo.com/lifestyle/8-substances-that-may-be-killing-your-erection-127187355828.html | title=8 Substances That May be Killing Your Erection | date=26 August 2015 }}</ref><ref>{{cite web | url=https://www.webmd.com/erectile-dysfunction/guide/drugs-linked-erectile-dysfunction | title=Drugs That Can Cause Erectile Dysfunction }}</ref>

The newer, second-generation H<sub>1</sub>-antihistamines are far more selective for peripheral histamine H<sub>1</sub>-receptors and have a 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" />

Continuous and/or cumulative use of [[anticholinergic]] medications, including first-generation antihistamines, is associated with a higher risk for cognitive decline and dementia in older people.<ref>{{cite journal | vauthors = Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB | display-authors = 6 | title = Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study | journal = JAMA Internal Medicine | volume = 175 | issue = 3 | pages = 401–407 | date = March 2015 | pmid = 25621434 | pmc = 4358759 | doi = 10.1001/jamainternmed.2014.7663 | author5-link = Rebecca Hubbard }}</ref><ref>{{cite journal |author1=Carrière, I |author2=Fourrier-Reglat, A |author3=Dartigues, J-F |author4=Rouaud, O |author5=Pasquier, F |author6=Ritchie, K |author7=Ancelin, M-L |title=Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study |journal=Archives of Internal Medicine |date=July 2009 |volume=169 |issue=14 |pages=1317–1324 |doi=10.1001/archinternmed.2009.229 |pmid=19636034 |pmc=2933398 }}</ref>

==Pharmacology==
===Anti-allergy activity===
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 allergen cross-links [[Immunoglobulin E]], tyrosine kinases rapidly signal into the cell, leading to cell [[degranulation]] and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, the histamine can react with local or widespread tissues through [[histamine receptor]]s.{{Citation needed|date=January 2018}}

Histamine, acting on H<sub>1</sub>-receptors, produces [[itch|pruritus]], [[vasodilation]], [[hypotension]], [[Flushing (physiology)|flushing]], [[headache]], [[bradycardia]], [[bronchoconstriction]], increase in [[vascular permeability]] and potentiation of pain.<ref name=":1">{{cite journal | vauthors = Simons FE | title = Advances in H1-antihistamines | journal = The New England Journal of Medicine | volume = 351 | issue = 21 | pages = 2203–17 | date = November 2004 | 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 of life-threatening severity. Additional administration of [[epinephrine]], often in the form of an [[autoinjector]], is required by people with such hypersensitivities.<ref name="u761">{{cite journal | last=Shaker | first=Marcus S. | last2=Wallace | first2=Dana V. | last3=Golden | first3=David B. K. | last4=Oppenheimer | first4=John | last5=Bernstein | first5=Jonathan A. | last6=Campbell | first6=Ronna L. | last7=Dinakar | first7=Chitra | last8=Ellis | first8=Anne | last9=Greenhawt | first9=Matthew | last10=Khan | first10=David A. | last11=Lang | first11=David M. | last12=Lang | first12=Eddy S. | last13=Lieberman | first13=Jay A. | last14=Portnoy | first14=Jay | last15=Rank | first15=Matthew A. | last16=Stukus | first16=David R. | last17=Wang | first17=Julie | display-authors=3 | title=Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis | journal=The Journal of Allergy and Clinical Immunology | volume=145 | issue=4 | date=2020 | issn=1097-6825 | pmid=32001253 | doi=10.1016/j.jaci.2020.01.017 | pages=1082–1123}}</ref>

===Sedative and hypnotic activity===
{| class="wikitable"
|+ Comparison of selected sedating and hypnotic antihistamines
! Antihistamine
! Brand name
! Dose<sup>a</sup>
! Time to peak
! Half-life<sup>b</sup>
! Metabolism
! Selective?
! Anticholinergic?
|-
| [[Cyproheptadine]]
| Periactin
| 4–8&nbsp;mg
| 1–3 hours
| 8–9 hours
| Unknown
| No
| Yes
|-
| [[Diphenhydramine]]
| Benadryl
| 50&nbsp;mg
| 2–3 hours
| 2–9 hours
| CYP2D6, others
| No
| Yes
|-
| [[Doxepin]] (low-dose)
| Silenor
| 3–6&nbsp;mg
| 2–3 hours
| 17 hours<sup>c</sup>
| CYP2D6, others
| Yes (at low doses)
| No (at low doses)
|-
| [[Doxylamine]]
| Unisom
| 25&nbsp;mg
| 2–3 hours
| 10–12 hours
| CYP2D6, others
| No
| Yes
|-
| [[Hydroxyzine]]
| Atarax, Vistaril
| 25–100&nbsp;mg
| 2 hours
| 20 hours
| ADH, CYP3A4, others
| Yes (at low doses)
| No
|-
| [[Mirtazapine]]
| Remeron
| 7.5–15&nbsp;mg
| 2 hours
| 20–40 hours
| CYP2D6, others
| No
| No
|-
| [[Quetiapine]]<sup>e</sup>
| Seroquel
| 25–200&nbsp;mg
| 1.5 hours
| 7 hours<sup>d</sup>
| CYP3A4
| No
| No (at low doses)
|-
| colspan="8" style="width: 1px; background-color:#eaecf0;" | '''Footnotes:''' <sup>a</sup> = For sleep/sedation. <sup>b</sup> = In adults. <sup>c</sup> Active metabolite nordoxepin half-life is 31 hours. <sup>d</sup> Active metabolite norquetiapine half-life is 9–12 hours. <sup>e</sup> Not recommended per literature reviews. '''Sources:''' See individual articles for references. See also selected reviews.<ref name="pmid23229983">{{cite journal | vauthors = Vande Griend JP, Anderson SL | title = Histamine-1 receptor antagonism for treatment of insomnia | journal = J Am Pharm Assoc (2003) | volume = 52 | issue = 6 | pages = e210–9 | date = 2012 | pmid = 23229983 | doi = 10.1331/JAPhA.2012.12051 }}</ref><ref name="pmid28671376">{{cite journal | vauthors = Matheson E, Hainer BL | title = Insomnia: Pharmacologic Therapy | journal = Am Fam Physician | volume = 96 | issue = 1 | pages = 29–35 | date = July 2017 | pmid = 28671376 }}</ref><ref name="pmid26609210">{{cite journal | vauthors = Lie JD, Tu KN, Shen DD, Wong BM | title = Pharmacological Treatment of Insomnia | journal = P T | volume = 40 | issue = 11 | pages = 759–71 | date = November 2015 | pmid = 26609210 | pmc = 4634348 }}</ref>
|}

Other non-selective sedating antihistamines used as hypnotics include the antihistamines [[chlorpheniramine]] and [[promethazine]], the [[antidepressant]]s [[amitriptyline]], [[trimipramine]], and [[trazodone]], and the [[antipsychotic]]s [[olanzapine]], [[risperidone]], and [[chlorpromazine]], among others.<ref name="pmid23229983" /><ref name="KrystalRichelsonRoth2013">{{cite journal | vauthors = Krystal AD, Richelson E, Roth T | title = Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications | journal = Sleep Med Rev | volume = 17 | issue = 4 | pages = 263–272 | date = August 2013 | pmid = 23357028 | doi = 10.1016/j.smrv.2012.08.001 | url = }}</ref>

==First-generation (unselective)==
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 [[alpha adrenergic receptor|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 when 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 [[Ernest Fourneau]] 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 |author2=Daniel Bovet  |year=1933 |title=Recherches sur l'action sympathicolytique d'un nouveau dérivé du dioxane |journal=Archives Internationales de Pharmacodynamie et de Thérapie |issn=0003-9780 |volume=46 |pages=178–91|author2-link=Daniel Bovet }}</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)
* [[Chloropyramine]]
* [[Antazoline]]
* [[Tripelennamine]]
 |-
 | [[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 |chapter-url=https://books.google.com/books?id=NHQQBMM-qMEC&pg=PA1004 |year=2007 |editor1=William O. Foye |editor2=Thomas L. Lemke |editor3=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]]
* [[Orphenadrine]]
* [[Bromazine]]
* [[Clemastine]]
* [[Dimenhydrinate]]
 |-
 | [[Amine#Drugs|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]]
* [[Dexbrompheniramine]]
* [[Brompheniramine]]
* [[Triprolidine]]
* [[Dimetindene]]
 |-
 | [[Piperazines]] || These compounds are structurally related to the ethylenediamines and the ethanolamines, and produce significant [[anticholinergic]] adverse effects with the exception of hydroxyzine, which has low to no affinity for [[muscarinic acetylcholine receptor]]s and therefore produces negligible anticholinergic side-effects.<ref>{{Cite journal|last1=Kubo|first1=Nobuo|last2=Shirakawa|first2=Osamu|last3=Kuno|first3=Takayoshi|last4=Tanaka|first4=Chikako|date=1987|title=Antimuscarinic Effects of Antihistamines: Quantitative Evaluation by Receptor-Binding Assay|journal=The Japanese Journal of Pharmacology|volume=43|issue=3|pages=277–282|doi=10.1254/jjp.43.277|pmid=2884340|doi-access=free}}</ref> 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 [[tetracyclic antidepressant|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]]
|}

===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., CH<sub>3</sub>

[[File: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 oriented in different planes
** For example, the 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 ==
Second-generation H<sub>1</sub>-antihistamines are newer drugs that are much more selective for peripheral H<sub>1</sub> receptors as opposed to the [[central nervous system]] H<sub>1</sub> receptors and [[cholinergic receptors]]. This selectivity significantly reduces the occurrence of adverse drug reactions, such as sedation, while still providing effective relief of allergic conditions.
Most of these compounds have peripheral selectivity because they are [[zwitterion]]ic at physiological pH (around pH 7.4). As such, they are very polar, meaning they are less likely to cross the [[blood–brain barrier]] and act mainly outside the central nervous system.

Examples of systemic second-generation antihistamines include:
{{div col|colwidth=20em|small=yes}}
* [[Acrivastine]] (Benadryl Allergy Relief (UK), Semprex-D (US))
* [[Astemizole]] (Hismanal) – withdrawn
* [[Bepotastine]] (Talion, Bepreve)<ref>{{Cite web|url=https://www.drugs.com/monograph/bepotastine.html|title=Bepotastine Monograph for Professionals}}</ref>
* [[Bilastine]] (Blexten, Fortecal, Lendin)
* [[Cetirizine]] (Zyrtec, Benadryl Allergy One a Day Relief (UK))<ref>{{Cite web|url=https://www.drugs.com/monograph/cetirizine.html|title = Cetirizine Monograph for Professionals}}</ref>
* [[Desloratadine]] (Aerius)<ref name="pmid16109168">{{cite journal | vauthors = Howell G, West L, Jenkins C, Lineberry B, Yokum D, Rockhold R | title = In vivo antimuscarinic actions of the third generation antihistaminergic agent, desloratadine | journal = BMC Pharmacology | volume = 5 | pages = 13 | date = August 2005 | pmid = 16109168 | pmc = 1192807 | doi = 10.1186/1471-2210-5-13 | doi-access = free }}</ref><ref>{{Cite web|url=https://www.drugs.com/monograph/desloratadine.html|title = Desloratadine Monograph for Professionals}}</ref>
* [[Ebastine]] (Evastin, Kestine, Ebastel, Aleva, Ebatrol)
* [[Fexofenadine]] (Allegra)<ref name="pmid12575922">{{cite journal | vauthors = Vena GA, Cassano N, Filieri M, Filotico R, D'Argento V, Coviello C | title = Fexofenadine in chronic idiopathic urticaria: a clinical and immunohistochemical evaluation | journal = International Journal of Immunopathology and Pharmacology | volume = 15 | issue = 3 | pages = 217–224 | date = September 2002 | pmid = 12575922 | doi = 10.1177/039463200201500308 | s2cid = 23060714 }}</ref><ref>{{Cite web|url=https://www.drugs.com/monograph/fexofenadine.html|title = Fexofenadine Monograph for Professionals}}</ref>
* [[Ketotifen]] (Zaditor) – also [[mast cell stabilizer]];<ref>{{Cite web|url=https://www.drugs.com/monograph/ketotifen.html|title = Ketotifen Monograph for Professionals}}</ref> sometimes classified as a first-generation antihistamine, see [[Ketotifen#Classification|Ketotifen § Classification]]
* [[Levocetirizine]] (Xyzal)<ref name="pmid16445787">{{cite journal | vauthors = 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 | journal = The British Journal of Dermatology | volume = 154 | issue = 3 | pages = 533–8 | date = March 2006 | pmid = 16445787 | doi = 10.1111/j.1365-2133.2005.07049.x | s2cid = 35041518 }}</ref><ref>{{Cite web|url=https://www.drugs.com/monograph/levocetirizine.html|title=Levocetirizine Monograph for Professionals}}</ref>
* [[Loratadine]] (Claritin)<ref>{{Cite web|url=https://www.drugs.com/monograph/loratadine.html|title = Loratadine Monograph for Professionals}}</ref>
* [[Mizolastine]] (Mizollen)
* [[Quifenadine]] (Phencarol, Фенкарол)
* [[Rupatadine]] (Rupafin)
* [[Terfenadine]] (Seldane (US), Triludan (UK), and Teldane (Australia)) – withdrawn
{{div col end}}

Examples of topical second-generation antihistamines include:
{{div col|colwidth=10em|small=yes}}
* [[Azelastine]]<ref>{{Cite web|url=https://www.drugs.com/monograph/azelastine.html|title = Azelastine Monograph for Professionals}}</ref>
* [[Levocabastine]]
* [[Olopatadine]]<ref>{{Cite web|url=https://www.drugs.com/monograph/olopatadine.html|title=Olopatadine Monograph for Professionals}}</ref>
{{div col end}}

==Regulation==

===Over-the-counter===
H<sub>1</sub> receptor antagonists that are approved for [[over-the-counter]] sale in the United States include the following.<ref name="FDA">{{cite web | url = https://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM135688.pdf | title = OTC Active Ingredients | date = 7 April 2010 | publisher = United States Food and Drug Administration }}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}</ref>

====First-generation====
Common/marketed:

* [[Brompheniramine]] (Dimetapp, Dimetane)
* [[Chlorpheniramine]] (Chlor-Trimeton)
* [[Dimenhydrinate]] (Dramamine, Gravol) – combination of [[diphenhydramine]] and [[8-chlorotheophylline]]
* [[Diphenhydramine]] (Benadryl)
* [[Doxylamine]] (Unisom)

Uncommon/discontinued:

* [[Chlorcyclizine]]
* [[Dexbrompheniramine]]
* [[Dexchlorpheniramine]]
* [[Methapyrilene]]
* [[Phenindamine]]
* [[Pheniramine]]
* [[Phenyltoloxamine]]
* [[Pyrilamine]]
* [[Thenyldiamine]]
* [[Thonzylamine]]
* [[Triprolidine]]

====Second-generation<span class="anchor" id="Second-generation and third-generation (selective)"></span>====
* [[Cetirizine]] (Zyrtec)
* [[Fexofenadine]] (Allegra)
* [[Levocetirizine]] (Xyzal)
* [[Loratadine]] (Alavert, Claritin)

== See also ==
* [[H2 antagonist|H<sub>2</sub>-receptor antagonist]]
* [[H3 antagonist|H<sub>3</sub>-receptor antagonist]]

== References ==
{{Reflist}}

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

{{Antihistamines}}
{{Histaminergics}}
{{Major Drug Groups}}
{{Neuromodulation}}

{{DEFAULTSORT:H1 Antagonist}}
[[Category:H1 receptor antagonists| ]]