H1 antagonist

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.

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

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."[5]

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, and psychosis.[4]

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]

Multiple studies have shown that H1 antihistamines, including fexofenadine, interfere with exercise induced muscle growth and repair

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.

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.

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. 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.[6][7][8]

First-generation (non-selective)

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.[9] 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
EthylenediaminesEthylenediamines were the first group of clinically effective H1-antihistamines developed.
  • Mepyramine (pyrilamine)
  • Chloropyramine
  • Antazoline
  • Tripelennamine
EthanolaminesDiphenhydramine 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][10]
  • Diphenhydramine
  • Carbinoxamine
  • Doxylamine
  • Orphenadrine
  • Bromazine
  • Clemastine
  • Dimenhydrinate
AlkylaminesThe 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.[10] Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse effects, but relatively greater incidence of paradoxical central nervous system (CNS) stimulation.[4]
  • Pheniramine
  • Chlorphenamine (chlorpheniramine)
  • Dexchlorpheniramine
  • Dexbrompheniramine
  • Brompheniramine
  • Triprolidine
  • Dimetindene
PiperazinesThese 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.[11] 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.[10]
Tricyclics and TetracyclicsThese compounds differ from the phenothiazine antipsychotics in the ring-substitution and chain characteristics.[10] 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.
  • 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., 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

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. The reason for their peripheral selectivity is that most of these compounds are zwitterionic at physiological pH (around pH 7.4). As such, they are very polar, meaning that they are less likely to cross the blood–brain barrier and act mainly outside the central nervous system. However, some second-generation antihistamines, notably cetirizine, can interact with CNS psychoactive drugs such as bupropion and benzodiazepines.[12]

Examples of systemic second-generation antihistamines include:

  • Acrivastine (Benadryl Allergy Relief (UK), Semprex-D (US))
  • Astemizole (Hismanal) - withdrawn
  • Bepotastine (Talion, Bepreve)[13]
  • Bilastine (Blexten, Fortecal)
  • Cetirizine (Zyrtec, Benadryl Allergy One a Day Relief (UK))[14]
  • Desloratadine (Aerius) [15][16]
  • Ebastine (Evastin, Kestine, Ebastel, Aleva, Ebatrol)
  • Fexofenadine (Allegra) [17][18]
  • Ketotifen (Zaditor) - also mast cell stabilizer[19]
  • Levocetirizine (Xyzal) [20][21]
  • Loratadine (Claritin)[22]
  • Mizolastine (Mizollen)
  • Quifenadine (Phencarol, Фенкарол)
  • Rupatadine (Rupafin)
  • Terfenadine (Seldane (US), Triludan (UK), and Teldane (Australia)) - withdrawn

Examples of topical second-generation antihistamines include:

  • Azelastine[23]
  • Levocabastine
  • Olopatadine[24]

Regulation

Over-the-counter

H1 receptor antagonists that are approved for over-the-counter sale, at least in the United States, include the following.[25]

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
  • Cetirizine (Zyrtec)
  • Fexofenadine (Allegra)
  • Levocetirizine (Xyzal)
  • Loratadine (Alavert, Claritin)

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. 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. Rossi S (Ed.) (2004). Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2
  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. PMID 15415236.
  6. 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.
  7. Matheson E, Hainer BL (July 2017). "Insomnia: Pharmacologic Therapy". Am Fam Physician. 96 (1): 29–35. PMID 28671376.
  8. Lie JD, Tu KN, Shen DD, Wong BM (November 2015). "Pharmacological Treatment of Insomnia". P T. 40 (11): 759–71. PMC 4634348. PMID 26609210.
  9. 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.
  10. 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.
  11. 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.
  12. "Drug Interaction Report". drugs.com. Retrieved 28 January 2017.
  13. "Bepotastine Monograph for Professionals".
  14. "Cetirizine Monograph for Professionals".
  15. 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.
  16. "Desloratadine Monograph for Professionals".
  17. 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.
  18. "Fexofenadine Monograph for Professionals".
  19. "Ketotifen Monograph for Professionals".
  20. 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.
  21. "Levocetirizine Monograph for Professionals".
  22. "Loratadine Monograph for Professionals".
  23. "Azelastine Monograph for Professionals".
  24. "Olopatadine Monograph for Professionals".
  25. "OTC Active Ingredients" (PDF). United States Food and Drug Administration. 7 April 2010.
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