Wikipedia

H1antagonist

H1antagonists,also calledH1blockers,are a class ofmedicationsthat block the action ofhistamineat theH1receptor,helping to relieveallergic reactions.Agents where the main therapeutic effect is mediated by negative modulation of histamine receptors are termedantihistamines;other agents may have antihistaminergic action but are not true antihistamines.[citation needed]

In common use, the term "antihistamine" refers only to H1-antihistamines. Virtually all H1-antihistamines function asinverse agonistsat the histamine H1-receptor, as opposed to neutralantagonists,as was previously believed.[1][2][3]

Medical uses

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H1-antihistamines are clinically used in the treatment of histamine-mediated allergic conditions. These indications may include:[4]

H1-antihistamines can be administered topically (through theskin,nose,oreyes) 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 includediphenhydramine(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."[5]

Side effects

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Adverse drug reactionsare most commonly associated with the first-generation H1-antihistamines. This is due to their relative lack of selectivity for the H1-receptor and their ability to cross theblood–brain barrier.

The most common adverse effect is sedation; this "side-effect" is utilized in manyOTCsleeping-aid preparations. Other common adverse effects in first-generation H1-antihistamines include dizziness,tinnitus,blurred vision,euphoria,incoordination,anxiety,increased appetite leading toweight gain,insomnia,tremor,nauseaand vomiting,constipation,diarrhea,dry mouth, and dry cough. Infrequent adverse effects include urinary retention,palpitations,hypotension,headache,hallucination,psychosisanderectile dysfunction.[4][6][7]

The newer, second-generation H1-antihistamines are far more selective for peripheral histamine H1-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.[4]

Continuous and/or cumulative use ofanticholinergicmedications, including first-generation antihistamines, is associated with higher risk for cognitive decline and dementia in older people.[8][9]

Pharmacology

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In type I hypersensitivity allergic reactions, anallergen(a type ofantigen) interacts with and cross-links surface IgEantibodiesonmast cellsandbasophils.Once the allergen cross-linksImmunoglobulin E,tyrosine kinases rapidly signal into the cell, leading to celldegranulationand 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 throughhistamine receptors.[citation needed]

Histamine, acting on H1-receptors, producespruritus,vasodilation,hypotension,flushing,headache,bradycardia,bronchoconstriction,increase invascular permeabilityand potentiation of pain.[2]

While H1-antihistamines help against these effects, they work only if taken before contact with the allergen. In severe allergies, such asanaphylaxisorangioedema,these effects may be of life-threatening severity. Additional administration ofepinephrine,often in the form of anautoinjector,is required by people with such hypersensitivities.[10]

Comparison of selected sedating antihistamines
Antihistamine Dosea Time to peak Half-lifeb Metabolism Anticholinergic
Diphenhydramine 50 mg 2–3 hours 2–9 hours CYP2D6, others Yes
Doxylamine 25 mg 2–3 hours 10–12 hours CYP2D6, others Yes
Hydroxyzine 25–100 mg 2 hours 20 hours ADH, CYP3A4, others No
Doxepin 3–6 mg 2–3 hours 17 hoursc CYP2D6, others No (at low doses)
Mirtazapine 7.5–15 mg 2 hours 20–40 hours CYP2D6, others No
Quetiapinee 25–200 mg 1.5 hours 7 hoursd CYP3A4 No (at low doses)
Footnotes:a= For sleep/sedation.b= In adults.cActive metabolite nordoxepin half-life is 31 hours.dActive metabolite norquetiapine half-life is 9–12 hours.eNot recommended per literature reviews.Sources:See individual articles for references. See also selected reviews.[11][12][13]

First-generation (unselective)

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These are the oldest H1-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 muscarinicacetylcholine receptor(anticholinergic) antagonists as well. These agents also commonly have action atα-adrenergic receptorsand/or5-HT receptors.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 H1-antihistamines. Patient response and occurrence of adverse drug reactions vary greatly between classes and between agents within classes.

Classes

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The first H1-antihistamine discovered waspiperoxan,byErnest FourneauandDaniel Bovet(1933) in their efforts to develop aguinea piganimal model foranaphylaxisat thePasteur InstituteinParis.[14]Bovet went on to win the 1957Nobel Prize in Physiology or Medicinefor his contribution. Following their discovery, the first-generation H1-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 Description Examples
Ethylenediamines Ethylenediamines were the first group of clinically effective H1-antihistamines developed.
Ethanolamines Diphenhydramine was the prototypical agent in this group. Significantanticholinergicadverse effects, as well as sedation, are observed in this group but the incidence of gastrointestinal adverse effects is relatively low.[4][15]
Alkylamines Theisomerismis a significant factor in the activity of the agents in this group.E-triprolidine, for example, is 1000-fold more potent thanZ-triprolidine. This difference relates to the positioning and fit of the molecules in the histamine H1-receptor binding site.[15]Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse effects, but relatively greater incidence of paradoxicalcentral nervous system(CNS) stimulation.[4]
Piperazines These compounds are structurally related to the ethylenediamines and the ethanolamines, and produce significantanticholinergicadverse effects with the exception of hydroxyzine, which has low to no affinity formuscarinic acetylcholine receptorsand therefore produces negligible anticholinergic side-effects.[16]Compounds from this group are often used for motion sickness, vertigo, nausea, and vomiting. The second-generation H1-antihistaminecetirizinealso belongs to this chemical group.[15]
TricyclicsandTetracyclics These compounds differ from thephenothiazineantipsychoticsin the ring-substitution and chain characteristics.[15]They are also structurally related to thetricyclic antidepressants(andtetracyclics), explaining the H1-antihistaminergic adverse effects of those three drug classes and also the poor tolerability profile of tricyclic H1-antihistamines. The second-generation H1-antihistamine loratadine was derived from compounds in this group.

Common structural features

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  • 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


X = N, R1 = R2 = small alkyl groups
X = C
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

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Second-generation H1-antihistamines are newer drugs that are much more selective for peripheral H1receptors as opposed to thecentral nervous systemH1receptors andcholinergic receptors.This selectivity significantly reduces the occurrence of adverse drug reactions, such as sedation, while still providing effective relief of allergic conditions. The reason for their peripheral selectivity is that most of these compounds arezwitterionicat physiological pH (around pH 7.4). As such, they are very polar, meaning that they are less likely to cross theblood–brain barrierand act mainly outside the central nervous system.

Examples of systemic second-generation antihistamines include:

Examples of topical second-generation antihistamines include:

Regulation

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Over-the-counter

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H1receptor antagonists that are approved forover-the-countersale in the United States, include the following.[30]

First-generation

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Common/marketed:

Uncommon/discontinued:

Second-generation

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See also

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References

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  1. ^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.doi:10.1046/j.0954-7894.2002.01314.x.PMID11972592.S2CID11849647.
  2. ^abSimons FE (November 2004). "Advances in H1-antihistamines".The New England Journal of Medicine.351(21): 2203–17.doi:10.1056/NEJMra033121.PMID15548781.
  3. ^Khilnani G, Khilnani AK (September 2011)."Inverse agonism and its therapeutic significance".Indian Journal of Pharmacology.43(5): 492–501.doi:10.4103/0253-7613.84947.PMC3195115.PMID22021988.
  4. ^abcdeRossi S (Ed.) (2004).Australian Medicines Handbook2004.Adelaide:Australian Medicines Handbook.ISBN0-9578521-4-2[page needed]
  5. ^Hoagland RJ, Deitz EN, Myers PW, Cosand HC (May 1950). "Antihistaminic drugs for colds; evaluation based on a controlled study".Journal of the American Medical Association.143(2): 157–60.doi:10.1001/jama.1950.02910370007003.PMID15415236.
  6. ^"8 Substances That May be Killing Your Erection".26 August 2015.
  7. ^"Drugs That Can Cause Erectile Dysfunction".
  8. ^Gray SL, Anderson ML, Dublin S, Hanlon JT,Hubbard R,Walker R, et al. (March 2015)."Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study".JAMA Internal Medicine.175(3): 401–407.doi:10.1001/jamainternmed.2014.7663.PMC4358759.PMID25621434.
  9. ^Carrière, I; Fourrier-Reglat, A; Dartigues, J-F; Rouaud, O; Pasquier, F; Ritchie, K; Ancelin, M-L (July 2009)."Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study".Archives of Internal Medicine.169(14): 1317–1324.doi:10.1001/archinternmed.2009.229.PMC2933398.PMID19636034.
  10. ^Shaker, Marcus S.; Wallace, Dana V.; Golden, David B. K.; et al. (2020). "Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis".The Journal of Allergy and Clinical Immunology.145(4): 1082–1123.doi:10.1016/j.jaci.2020.01.017.ISSN1097-6825.PMID32001253.
  11. ^Vande Griend JP, Anderson SL (2012). "Histamine-1 receptor antagonism for treatment of insomnia".J Am Pharm Assoc (2003).52(6): e210–9.doi:10.1331/JAPhA.2012.12051.PMID23229983.
  12. ^Matheson E, Hainer BL (July 2017). "Insomnia: Pharmacologic Therapy".Am Fam Physician.96(1): 29–35.PMID28671376.
  13. ^Lie JD, Tu KN, Shen DD, Wong BM (November 2015)."Pharmacological Treatment of Insomnia".P T.40(11): 759–71.PMC4634348.PMID26609210.
  14. ^Fourneau, Ernest;Daniel Bovet(1933). "Recherches sur l'action sympathicolytique d'un nouveau dérivé du dioxane".Archives Internationales de Pharmacodynamie et de Thérapie.46:178–91.ISSN0003-9780.
  15. ^abcdNelson, Wendel L. (2007)."Antihistamines and Related Antiallergic and Antiulcer Agents".In William O. Foye; Thomas L. Lemke; David A. Williams (eds.).Foye's Principles of Medicinal Chemistry.Hagerstown, Maryland:Lippincott Williams & Wilkins.pp. 1004–1027.ISBN978-0-7817-6879-5.OCLC149596645.
  16. ^Kubo, Nobuo; Shirakawa, Osamu; Kuno, Takayoshi; Tanaka, Chikako (1987)."Antimuscarinic Effects of Antihistamines: Quantitative Evaluation by Receptor-Binding Assay".The Japanese Journal of Pharmacology.43(3): 277–282.doi:10.1254/jjp.43.277.PMID2884340.
  17. ^"Bepotastine Monograph for Professionals".
  18. ^"Cetirizine Monograph for Professionals".
  19. ^Howell G, West L, Jenkins C, Lineberry B, Yokum D, Rockhold R (August 2005)."In vivo antimuscarinic actions of the third generation antihistaminergic agent, desloratadine".BMC Pharmacology.5:13.doi:10.1186/1471-2210-5-13.PMC1192807.PMID16109168.
  20. ^"Desloratadine Monograph for Professionals".
  21. ^Vena GA, Cassano N, Filieri M, Filotico R, D'Argento V, Coviello C (September 2002). "Fexofenadine in chronic idiopathic urticaria: a clinical and immunohistochemical evaluation".International Journal of Immunopathology and Pharmacology.15(3): 217–224.doi:10.1177/039463200201500308.PMID12575922.S2CID23060714.
  22. ^"Fexofenadine Monograph for Professionals".
  23. ^"Ketotifen Monograph for Professionals".
  24. ^Nettis E, Colanardi MC, Barra L, Ferrannini A, Vacca A, Tursi A (March 2006). "Levocetirizine in the treatment of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study".The British Journal of Dermatology.154(3): 533–8.doi:10.1111/j.1365-2133.2005.07049.x.PMID16445787.S2CID35041518.
  25. ^"Levocetirizine Monograph for Professionals".
  26. ^"Loratadine Monograph for Professionals".
  27. ^"Azelastine Monograph for Professionals".
  28. ^Al-Ahmad, Mona; Hassab, Mohammed; Al Ansari, Ali (21 December 2020). "Allergic and Non-allergic Rhinitis".Textbook of Clinical Otolaryngology.Cham: Springer International Publishing. pp. 241–252.doi:10.1007/978-3-030-54088-3_22.ISBN978-3-030-54087-6.S2CID234142758.Intranasal H1 antihistamines such as azelastine are effective for controlling nasal symptoms. They need to be applied twice daily.
  29. ^"Olopatadine Monograph for Professionals".
  30. ^"OTC Active Ingredients"(PDF).United States Food and Drug Administration. 7 April 2010.
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