An antihistamine is a type of pharmaceutical drug that opposes the activity of histamine receptors in the body. Antihistamines are subclassified according to the histamine receptor that they act upon: the two largest classes of antihistamines are H1-antihistamines and H2-antihistamines. Antihistamines that target the histamine H1-receptor are used to treat allergic reactions in the nose (e.g., itching, runny nose, and sneezing) as well as for insomnia. They are sometimes also used to treat motion sickness or vertigo caused by problems with the inner ear. Antihistamines that target the histamine H2-receptor are used to treat gastric acid conditions (e.g., peptic ulcers and acid reflux). H1-antihistamines work by binding to histamine H1 receptors in mast cells, smooth muscle, and endothelium in the body as well as in the tuberomammillary nucleus in the brain; H2-antihistamines bind to histamine H2 receptors in the upper gastrointestinal tract, primarily in the stomach.
Histamine receptors exhibit constitutive activity, so antihistamines can function as either a neutral receptor antagonist or an inverse agonist at histamine receptor. Only a few currently marketed H1-antihistamines are known to function as inverse agonists.
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Medical uses
Histamine produces increased vascular permeability, causing fluid to escape from capillaries into tissues, which leads to the classic symptoms of an allergic reaction -- a runny nose and watery eyes. Histamine also promotes angiogenesis.
Antihistamines suppress the histamine-induced wheal response (swelling) and flare response (vasodilation) by blocking the binding of histamine to its receptors or reducing histamine receptor activity on nerves, vascular smooth muscle, glandular cells, endothelium, and mast cells.
Itching, sneezing, and inflammatory responses are suppressed by antihistamines that act on H1-receptors. In 2014 antihistamines such as desloratadine were found to be effective as adjuvants to standardized treatment of acne due to their anti-inflammatory properties and their ability to suppress sebum production.
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Types
H1-antihistamines
H1-antihistamines refer to compounds that inhibit the activity of the H1 receptor. Since the H1 receptor exhibits constitutive activity, H1-antihistamines can be either neutral receptor antagonists or inverse agonists. Normally, histamine binds to the H1 receptor and heightens the receptor's activity; the receptor antagonists work by binding to the receptor and blocking the activation of the receptor by histamine; by comparison, the inverse agonists bind to the receptor and reduce its activity, an effect which is opposite to histamine's.
The vast majority of marketed H1-antihistamines are receptor antagonists and only a minority of marketed compounds are inverse agonists at the receptor. Clinically, H1-antihistamines are used to treat allergic reactions and mast cell-related disorders. Sedation is a common side effect of H1-antihistamines that readily cross the blood-brain barrier; some of these drugs, such as diphenhydramine and doxylamine, are therefore used to treat insomnia. H1-antihistamines can also reduce inflammation, since the expression of NF-?B, the transcription factor the regulates inflammatory processes, is promoted by both the receptor's constitutive activity and agonist (i.e., histamine) binding at the H1 receptor.
Second-generation antihistamines cross the blood-brain barrier to a much lower degree than the first-generation antihistamines. Their main benefit is they primarily affect peripheral histamine receptors and therefore are less sedating. However, high doses can still induce the central nervous system drowsiness. Some second-generation antihistamines, notably cetirizine, can interact with CNS psychoactive drugs such as bupropion and benzodiazepines.
H1 antagonists
Examples of H1 antagonists include:
- Acrivastine (see Benadryl entry in this section)
- Azelastine
- Benadryl is a brand name for different H1 antagonist anitihistamine preparations in different regions: acrivastine is the active component of Benadryl Allergy Relief and cetirizine of Benadryl One a Day Relief in the UK; Benadryl is diphenhydramine in the US and Canada.(see http://www.benadryl.ca/adult-allergy-medicine/benadryl-caplets)
- Bilastine
- Bromodiphenhydramine
- Brompheniramine
- Buclizine
- Carbinoxamine
- Cetirizine (see Benadryl entry in this section)
- Chlorodiphenhydramine
- Chlorphenamine
- Chlorpromazine (antipsychotic)
- Clemastine
- Cyclizine
- Cyproheptadine
- Dexbrompheniramine
- Dexchlorpheniramine
- Dimenhydrinate (most commonly used as an antiemetic)
- Dimetindene
- Diphenhydramine (see Benadryl entry in this section)
- Doxylamine (most commonly used as an over-the-counter drug sedative)
- Ebastine
- Embramine
- Fexofenadine (Allegra)
- Hydroxyzine (Vistaril)
- Loratadine (Claritin)
- Meclizine (most commonly used as an antiemetic)
- Mirtazapine (primarily used to treat depression, also has antiemetic and appetite-stimulating effects)
- Olopatadine (used locally)
- Orphenadrine (a close relative of diphenhydramine used mainly as a skeletal muscle relaxant and anti-Parkinsons agent)
- Phenindamine
- Pheniramine
- Phenyltoloxamine
- Promethazine
- Quetiapine (antipsychotic; trade name Seroquel)
- Rupatadine
- Tripelennamine
- Triprolidine
H1 inverse agonists
The H1 receptor inverse agonists include:
- Cetirizine (doesn't cross the blood-brain barrier)
- Levocetirizine
- Desloratadine (doesn't cross the blood-brain barrier)
- Pyrilamine (crosses the blood-brain barrier; produces drowsiness)
H2-antihistamines
H2-antihistamines, like H1-antihistamines, occur as inverse agonists and neutral antagonists. They act on H2 histamine receptors found mainly in the parietal cells of the gastric mucosa, which are part of the endogenous signaling pathway for gastric acid secretion. Normally, histamine acts on H2 to stimulate acid secretion; drugs that inhibit H2 signaling thus reduce the secretion of gastric acid.
H2-antihistamines are among first-line therapy to treat gastrointestinal conditions including peptic ulcers and gastroesophageal reflux disease. Some formulations are available over the counter. Most side effects are due to cross-reactivity with unintended receptors. Cimetidine, for example, is notorious for antagonizing androgenic testosterone and DHT receptors at high doses.
Examples include:
- Cimetidine
- Famotidine
- Lafutidine
- Nizatidine
- Ranitidine
- Roxatidine
- Tiotidine
Research
These are experimental agents and do not yet have a defined clinical use, although a number of drugs are currently in human trials. H3-antihistamines have a stimulant and nootropic effect, whereas H4-antihistamines appear to have an immunomodulatory role.
H3-antihistamines
An H3-antihistamine is a classification of drugs used to inhibit the action of histamine at the H3 receptor. H3 receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic nerve terminals, which modulate the release of histamine. Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors in the cerebral cortex. Consequently, unlike the H1-antihistamines which are sedating, H3-antihistamines have stimulant and cognition-modulating effects.
Examples of selective H3-antihistamines include:
- Clobenpropit,
- ABT-239
- Ciproxifan,
- Conessine
- A-349,821.
- Thioperamide
H4-antihistamines
Examples:
- Thioperamide
- JNJ 7777120
- VUF-6002
Related agents
Histidine decarboxylase inhibitors
Inhibit the action of histidine decarboxylase:
- Tritoqualine
- Catechin
Mast cell stabilizers
Mast cell stabilizers are drugs which prevent mast cell degranulation.
- cromolyn sodium
- Nedocromil
- ?-agonists
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