Information AboutAntihistamine |
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In common use, the term antihistamine refers only to H1-receptor antagonists, also known as '''H1-antihistamines'''. It has been discovered that these H1-antihistamines are actually Inverse Agonist s at the histamine H1-receptor, rather than Antagonists ''per se''. (Leurs, Church & Taglialatela, 2002) PHARMACOLOGY In allergic reactions an Allergen (a type of Antigen ) interacts with and cross-links surface IgE 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 Pruritus , Vasodilatation , Hypotension , Flushing , Headache , Tachycardia , Bronchoconstriction , increases Vascular Permeability , potentiates Pain , and more. (Simons, 2004) While H1-antihistamines ameliorate these effects, it is only efficacious if administered prior to the allergen-challenge. In severe allergies, such as Anaphylaxis or Angioedema , these effects may be so severe as to be life-threatening. Epinephrine , often in the form of an autoinjector ( Epi-pen ), is required by people with such hypersensitivities. CLINICAL USE OF ANTIHISTAMINES Indications 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 reactions 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 most common adverse effect is sedation; this "side effect" is utilised in many s, Hypotension , Headache , Hallucination , and Psychosis . (Rossi, 2004) 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) FIRST-GENERATION H<SUB>1</SUB>-RECEPTOR ANTAGONISTS 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 α- 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 Ethylenediamines were the first group of clinically-effective H1-antihistamines developed.
Ethanolamines 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) 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. (Nelson, 2002) Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse effects, but relatively greater incidence of paradoxical CNS stimulation. (Rossi, 2004)
Piperazines 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) Tricyclics 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
X = N, R1 = R2 = small alkyl groups X = C X = CO
SECOND-GENERATION H<SUB>1</SUB>-RECEPTOR ANTAGONISTS 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. Systemic
Topical 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. THIRD-GENERATION H<SUB>1</SUB>-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. Systemic OTHER AGENTS Inhibitors of histamine release These agents appear to stabilise the mast cells to prevent degranulation and mediator release.
H2-receptor antagonists ''Main article: H2-receptor Antagonist '' Clinically-relevant histamine H2-receptors are found principally in the Parietal Cell s of the Gastric mucosa. H2-receptor "antagonists" are also Inverse Agonist s, rather than true Antagonists ; and are used to reduce the secretion of Gastric Acid . Examples include Cimetidine , Ranitidine , and Famotidine . H3- and H4-receptor antagonists These are experimental agents and do not yet have a defined clinical use. H3-receptors antagonists
H4-receptors antagonists Other agents with antihistaminergic activity Many drugs, used for other indications, possess unwanted antihistaminergic activity. These include Tricyclic Antidepressants , Antipsychotic s, ''etc''. SEE ALSO REFERENCES
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