Advances in H 1 -Antihistamines

This article reviews the molecular biology of the interaction of histamine with its H1-receptor and describes the concept that H1-antihistamines are not receptor antagonists but are inverse agonists i.e. they produce the opposite effect on the receptor to histamine. It then discourages the use of first-generation H1-antihistamines in clinical practice today for two main reasons. First, they are less effective than second generation H1-antihistamines. Second, they have unwanted side effects, particularly central nervous system and anti-cholinergic effects, and have the potential for causing severe toxic reactions which are not shared by second-generation H1-antihistamines. There are many efficacious and safe second-generation H1-antihistamines on the market for the treatment of allergic disease. Of the three drugs highlighted in this review, levocetirizine and fexofenadine are the most efficacious in humans in vivo. However, levocetirizine may cause somnolence in susceptible individuals while fexofenadine has a relatively short duration of action requiring twice daily administration for full all round daily protection. While desloratadine is less efficacious, it has the advantages of rarely causing somnolence and having a long duration of action. Lastly, all H1-antihistamines have anti-inflammatory effects but it requires regular daily dosing rather than dosing 'on-demand' for this effect to be clinically demonstrable.

Section: Discussionmentioning

confidence: 99%

Section: First-generation H1-antihistaminesmentioning

confidence: 99%

Pharmacology of Antihistamines

Church¹,

Church²

2011

“…Some of them like hydroxyzine and diphenhydramine had proven to be of particular benefit in urticaria and are still considered as possible choices in cases resistant to treatment[17]. A significant step forward was the synthesis of more complex compounds with improved pharmacokinetic and pharmacodynamic profiles: they hardly penetrated the blood-brain barrier, which makes them relatively free of the most bothersome adverse CNS effects (drowsiness, lassitude, dizziness, and incoordination), possessed higher specificity for the H 1 receptors, and had longer half-life, allowing a once daily dosing regimen[18]. They were referred to as second-generation H 1 -receptor antagonists, and whereas 2 of the earlier compounds (terfenedine and astemisol) were abandoned because of serious cardiac side effects, the "newest arrivals" (fexofenadine, desloratadine, and levocetirizine) took up the lead in prescription practices as "modern" second-generation drugs.…”

Section: Picking the Best Antihistamine For The Treatment Of Ciumentioning

confidence: 99%

Challenges in the Management of Chronic Urticaria

Popov¹

2011

The term "chronic idiopathic urticaria" denotes a spectrum of conditions with different poorly understood pathogenetic mechanisms in which the release of histamine plays a role. Nonsedating second-generation H1 antihistamines are postulated to be the first line of treatment of chronic idiopathic urticaria by national and international guidelines, but as control is not always achievable with the usually recommended doses, first-generation sedating antihistamines like hydroxyzine and diphenhydramine at high daily doses (200 mg) have been proposed as an alternative before resorting to treatment with systemic corticosteroids and other potentially hazardous agents. Our long time experience and recent research give us grounds to believe that increasing the doses of nonsedating H1 antihistamines up to fourfold improves significantly the chances of successful treatment. Our data suggest that the urticaria-associated discomfort is relieved by higher than conventional doses of levoce-tirizine and desloratadine in about 75% of the patients and that sedation/somnolence does not seem to be a major deterrent. The dose increase also improves the urticaria-specific quality of life. Contrary to the belief that individual patients may benefit from one antihistamine or another, we demonstrate that the drug with better ability to suppress the histamine skin effects in experiments in healthy volunteers (levocetirizine) is also superior in improving the different aspects of control of chronic urticaria (subjective and objective symptoms, quality of life) and that increasing its dose of up to fourfold may even paradoxically reduce the sense of sedation/somnolence in parallel with the relief of urticaria discomfort.

“…Through the H 1 receptor, histamine is involved in cell proliferation and differentiation, hematopoiesis, embryonic development, regeneration, and wound healing. It is a neurotransmitter, has anticonvulsant activity, and contributes to regulation of the sleep-waking cycle, energy and endocrine homeostasis, cognition and memory [1,2]. …”

mentioning

confidence: 99%

“…Histamine receptors have constitutive activity, which is defined as the ability to trigger downstream events, even in the absence of ligand binding. The active and inactive states of these receptors exist in equilibrium; at rest, the inactive state isomerizes with the active state and vice versa [2,3]. …”

mentioning

confidence: 99%

H1 Antihistamines: Current Status and Future Directions

Simon

Simons

2008

100

107

In this review, we compare and contrast the clinical pharmacology, efficacy, and safety of first-generation H1 antihistamines and second-generation H1 antihistamines. First-generation H1 antihistamines cross the blood-brain barrier, and in usual doses, they potentially cause sedation and impair cognitive function and psychomotor performance. These medications, some of which have been in use for more than 6 decades, have never been optimally investigated. Second-generation H1 antihistamines such as cetirizine, desloratadine, fexofenadine, levocetirizine, and loratadine cross the blood-brain barrier to a significantly smaller extent than their predecessors. The clinical pharmacology, efficacy, and safety of these medications have been extensively studied. They are therefore the H1 antihistamines of choice in the treatment of allergic rhinitis, allergic conjunctivitis, and urticaria. In the future, clinically advantageous H1 antihistamines developed with the aid of molecular techniques might be available.