Antihistamine

Antihistamines
Drug class
Histamine structure
Class identifiers
ATC code	R06
Mechanism of action	• Receptor antagonist  • Inverse agonist
Biological target	Histamine receptors  • HRH1  • HRH2  • HRH3  • HRH4
External links
MeSH	D006633

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.

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.

Types

H₁-antihistamines

Main article: H₁-antihistamine

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-κB, 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.

H₁ antagonists

Examples of H₁ antagonists include:

• Acrivastine
• Azelastine
• Bilastine
• Brompheniramine
• Buclizine
• Bromodiphenhydramine
• Carbinoxamine
• Chlorpromazine (antipsychotic)
• Cyclizine
• Chlorphenamine
• Chlorodiphenhydramine
• Clemastine
• Cyproheptadine
• Dexbrompheniramine
• Dexchlorpheniramine
• Dimenhydrinate (most commonly used as an antiemetic)
• Dimetindene
• Diphenhydramine (Benadryl)
• Doxylamine (most commonly used as an over-the-counter drug sedative)
• Ebastine
• Embramine
• Fexofenadine (Allegra)
• Hydroxyzine (Vistaril)
• Loratadine (Claritin)
• Meclozine (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

Main article: H₂-antihistamine

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

Main article: H₃-antihistamine

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

Main article: Mast cell stabilizer

Mast cell stabilizers are drugs which prevent mast cell degranulation.

• cromolyn sodium
• Nedocromil
• β-agonists

See also

• Antileukotriene

External links

• Histamine antagonist at the US National Library of Medicine Medical Subject Headings (MeSH)
• Antihistamine information at Allergy UK