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In 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 mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through [[histamine receptor]]s.

 

Histamine, acting on H₁-receptors, produces [[pruritis]], [[vasodilatation]], [[hypotension]], [[flushing]], [[headache]], [[tachycardia]], [[bronchoconstriction]], increases [[vascular permeability]], potentiates [[pain]], and more. (Simons, 2004)

 

 

H₁-antihistamines are clinically used in the treatment of histamine-mediated allergic conditions. Specifically, these indications may include: (Rossi, 2004)

 

Antihistamines can be administered topically (through the [[skin]], [[nose]], or [[eye]]s) or systemically, based on the nature of the allergic condition.

 

[[Adverse drug reaction]]s are most commonly associated with the first-generation H₁-antihistamines. This is due to their relative lack of selectivity for the H₁-receptor.

 

The newer second-generation H₁-antihistamines are far more selective for peripheral histamine H₁-receptors and, correspondingly, have a far improved 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. (Rossi, 2004)

 

These are the oldest 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]]-antagonists ([[anticholinergic]]) agents as well. These agents also commonly have action at &alpha;-[[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 compared with the second-generation H₁-antihistamines. Patient response and occurrence of adverse drug reactions vary greatly between classes and between agents within classes.

 

The first H₁-antihistamine discovered was [[piperoxan]], by Forneau and [[Daniel Bovet]] (1933) in their efforts to develop a [[guinea pig]] animal-model for [[anaphylaxis]]. 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.

 

Ethylenediamines were the first group of clinically-effective H₁-antihistamines developed.

 

 

Diphenhydramine was the prototypical agent in this group. Significant [[anticholinergic]] adverse effects, including sedation, are observed in this group but the incidence of gastrointestnal adverse effects is relatively low. (Nelson, 2002; Rossi, 2004)

 

 

The [[isomer|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. (Nelson, 2002) Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse effects, but relatively greater incidence of paradoxical [[central nervous system|CNS]] stimulation. (Rossi, 2004)

 

 

These compounds are structurally-related to the ethylenediamines and the ethanolamines; and produce significant [[anticholinergic]] adverse effects. 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. (Nelson, 2002)

 

 

These compounds differ from the [[phenothiazine]] [[antipsychotic]]s in the ring-substitution and chain characteristics. (Nelson, 2002) They are also structurally-related to the [[tricyclic antidepressant]]s, explaining the antihistaminergic adverse effects of those two 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 of classical antihistamine ===

* Amine is substituted with small alkyl groups eg CH3

 

'''X = N, R1 = R2 = small alkyl groups'''<br>

'''X = C'''<br>

'''X = CO'''

 

** for example, tricyclic ring system is slightly puckered and the two aromatic rings lie in different geometrical planes, given the drug a very high potency.

 

These are newer drugs that are much more selective for peripheral H₁ receptors in preference to the [[central nervous system]] histaminergic and cholinergic receptors. This selectivity significantly reduces the occurrence of adverse drug reactions compared with first-generation agents, while still providing effective relief of allergic conditions.

 

 

 

=== Common structural features of non-sedating antihistamines ===

Structure of these drugs varies from case to case. There is no common structural feature for the second generation H1-receptor antagonists.

 

These are the active enantiomer (levocetirizine, desloratadine) or metabolite (fexofenadine) derivatives of second-generation drugs intended to have increased efficacy with fewer [[adverse drug reaction]]s. Indeed, fexofenadine is associated with a decreased risk of [[cardiac arrhythmia]] compared to terfenadine. However, there is little evidence for any advantage of levocetirizine or desloratadine, compared to cetirizine or loratadine respectively.

 

 

These agents appear to stabilise the mast cells to prevent degranulation and mediator release.

* [[cromoglicate]] (cromolyn)

* [[nedocromil]]

 

''Main article: [[H2-receptor antagonist]]''

 

Clinically-relevant histamine H₂-receptors are found principally in the [[parietal cell]]s of the [[stomach|gastric]] mucosa. H₂-receptor "antagonists" are also [[inverse agonist]]s, rather than true [[receptor antagonist|antagonists]]; and are used to reduce the secretion of [[gastric acid]]. Examples include [[cimetidine]], [[ranitidine]], and [[famotidine]].

 

These are experimental agents and do not yet have a defined clinical use.

 

 

 

Many drugs, used for other indications, possess unwanted antihistaminergic activity. These include [[tricyclic antidepressants]], [[antipsychotic]]s, ''etc''.--->

 

* [[H2-receptor antagonist]]

 

* Forneau E, Bovet D (1933). Recherches sur l'action sympathicolytique d'un nouveau derive du dioxane. ''Arch Int Pharmacodyn'' '''46''', 178-91.

* Leurs R, Church MK, Taglialatela M (2002). H₁-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. ''Clin Exp Allergy'' '''32''', 489-98.

* Nelson, WL (2002). In Williams DA, Lemke TL (Eds.). ''Foye's Principles of Medicinal Chemistry'' (5 ed.). Philadelphia: Lippincott Williams & Wilkins. ISBN 0-683-30737-1

* Rossi S (Ed.) (2004). ''[[Australian Medicines Handbook]] 2004''. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2

 

{{สารต้านฮิสตามีน}}

 

[[bs:Antagonisti H1 receptora]]