H1 antagonist

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H1 antagonists, also called H1 blockers, are a class of medications that block the action of histamine at the H1 receptor, helping to relieve 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.[ citation needed ]

Contents

In common use, the term "antihistamine" refers only to H1-antihistamines. Virtually all H1-antihistamines function as inverse agonists at the histamine H1-receptor, as opposed to neutral antagonists, as was previously believed. [1] [2] [3]

Medical uses

H1-antihistamines are used clinically to treat histamine-mediated allergic conditions. These indications may include: [4]

First-generation H1-antihistamines can act on the central nervous system. As a result, they are also used for: [5]

H1-antihistamines can be administered topically (through the skin, nose, or eyes) 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." [6]

Side effects

Adverse drug reactions are 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 the blood–brain barrier.

The most common adverse effect is sedation; this "side-effect" is utilized in many OTC sleeping-aid preparations. Other common adverse effects in first-generation H1-antihistamines include dizziness, tinnitus, blurred vision, 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, palpitations, hypotension, headache, hallucination, psychosis and erectile dysfunction. [4] [7] [8]

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 of anticholinergic medications, including first-generation antihistamines, is associated with a higher risk for cognitive decline and dementia in older people. [9] [10]

Pharmacology

In type I hypersensitivity allergic reactions, an allergen (a type of antigen) interacts with and cross-links surface IgE antibodies on mast cells and basophils. 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 receptors.[ citation needed ]

Histamine, acting on H1-receptors, produces pruritus, vasodilation, hypotension, flushing, headache, bradycardia, bronchoconstriction, increase in vascular permeability and 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 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. [11]

Comparison of selected sedating antihistamines
AntihistamineDoseaTime to peakHalf-lifebMetabolismAnticholinergic
Diphenhydramine 50 mg2–3 hours2–9 hoursCYP2D6, othersYes
Doxylamine 25 mg2–3 hours10–12 hoursCYP2D6, othersYes
Hydroxyzine 25–100 mg2 hours20 hoursADH, CYP3A4, othersNo
Doxepin 3–6 mg2–3 hours17 hourscCYP2D6, othersNo (at low doses)
Mirtazapine 7.5–15 mg2 hours20–40 hoursCYP2D6, othersNo
Quetiapine e25–200 mg1.5 hours7 hoursdCYP3A4No (at low doses)
Footnotes:a = For sleep/sedation. b = In adults. c Active metabolite nordoxepin half-life is 31 hours. d Active metabolite norquetiapine half-life is 9–12 hours. e Not recommended per literature reviews. Sources: See individual articles for references. See also selected reviews. [12] [13] [14]

First-generation (unselective)

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 muscarinic acetylcholine receptor (anticholinergic) antagonists as well. These agents also commonly have action at α-adrenergic receptors and/or 5-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

The first H1-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. [15] Bovet went on to win the 1957 Nobel Prize in Physiology or Medicine for 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.

ClassDescriptionExamples
Ethylenediamines Ethylenediamines were the first group of clinically effective H1-antihistamines developed.
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. [4] [16]
Alkylamines The isomerism 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 H1-receptor binding site. [16] Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse effects, but relatively greater incidence of paradoxical central nervous system (CNS) stimulation. [4]
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 receptors and therefore produces negligible anticholinergic side-effects. [17] Compounds from this group are often used for motion sickness, vertigo, nausea, and vomiting. The second-generation H1-antihistamine cetirizine also belongs to this chemical group. [16]
Tricyclics and Tetracyclics These compounds differ from the phenothiazine antipsychotics in the ring-substitution and chain characteristics. [16] They are also structurally related to the tricyclic antidepressants (and tetracyclics), 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

Antihistamine.svg
X = N, R1 = R2 = small alkyl groups
X = C
X = CO

Second-generation

Second-generation H1-antihistamines are newer drugs that are much more selective for peripheral H1 receptors as opposed to the central nervous system H1 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 zwitterionic 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:

Examples of topical second-generation antihistamines include:

Regulation

Over-the-counter

H1 receptor antagonists that are approved for over-the-counter sale in the United States include the following. [30]

First-generation

Common/marketed:

Uncommon/discontinued:

Second-generation

See also

References

  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. PMID   11972592. S2CID   11849647.
  2. 1 2 Simons FE (November 2004). "Advances in H1-antihistamines". The New England Journal of Medicine. 351 (21): 2203–17. doi:10.1056/NEJMra033121. PMID   15548781.
  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 . PMC   3195115 . PMID   22021988.
  4. 1 2 3 4 5 Rossi S (Ed.) (2004). Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook. ISBN   0-9578521-4-2 [ page needed ]
  5. ↑ Takov, V; Tadi, P (January 2019). Motion Sickness (in StatPearls). PMID   30969528.
  6. ↑ 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. PMID   15415236.
  7. ↑ "8 Substances That May be Killing Your Erection". 26 August 2015.
  8. ↑ "Drugs That Can Cause Erectile Dysfunction".
  9. ↑ 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. PMC   4358759 . PMID   25621434.
  10. ↑ 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. PMC   2933398 . PMID   19636034.
  11. ↑ 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. ISSN   1097-6825. PMID   32001253.
  12. ↑ 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. PMID   23229983.
  13. ↑ Matheson E, Hainer BL (July 2017). "Insomnia: Pharmacologic Therapy". Am Fam Physician. 96 (1): 29–35. PMID   28671376.
  14. ↑ Lie JD, Tu KN, Shen DD, Wong BM (November 2015). "Pharmacological Treatment of Insomnia". P T. 40 (11): 759–71. PMC   4634348 . PMID   26609210.
  15. ↑ 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. ISSN   0003-9780.
  16. 1 2 3 4 Nelson, 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. ISBN   978-0-7817-6879-5. OCLC   149596645.
  17. ↑ 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 . PMID   2884340.
  18. ↑ "Bepotastine Monograph for Professionals".
  19. ↑ "Cetirizine Monograph for Professionals".
  20. ↑ 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 . PMC   1192807 . PMID   16109168.
  21. ↑ "Desloratadine Monograph for Professionals".
  22. ↑ 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. PMID   12575922. S2CID   23060714.
  23. ↑ "Fexofenadine Monograph for Professionals".
  24. ↑ "Ketotifen Monograph for Professionals".
  25. ↑ 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. PMID   16445787. S2CID   35041518.
  26. ↑ "Levocetirizine Monograph for Professionals".
  27. ↑ "Loratadine Monograph for Professionals".
  28. ↑ "Azelastine Monograph for Professionals".
  29. ↑ "Olopatadine Monograph for Professionals".
  30. ↑ "OTC Active Ingredients" (PDF). United States Food and Drug Administration. 7 April 2010.[ dead link ]
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