| Antihistamine | |
|---|---|
| Drug class | |
 Histamine structure | |
| Class identifiers | |
| Pronunciation | /ˌæntiˈhɪstəmiːn/ |
| ATC code | R06 |
| Mechanism of action | • Receptor antagonist • Inverse agonist |
| Biological target | Histamine receptors • HRH1 • HRH2 • HRH3 • HRH4 |
| External links | |
| MeSH | D006633 |
| Legal status | |
| In Wikidata | |
Antihistamines aredrugs which treatallergic rhinitis,common cold,influenza, and otherallergies.[1] Typically, people take antihistamines as an inexpensive,generic (not patented) drug that can be boughtwithout a prescription and provides relief fromnasal congestion,sneezing, orhives caused bypollen,dust mites, oranimal allergy with few side effects.[1] Antihistamines are usually for short-term treatment.[1] Chronic allergies increase the risk of health problems which antihistamines might not treat, includingasthma,sinusitis, andlower respiratory tract infection.[1] Consultation of a medical professional is recommended for those who intend to take antihistamines for longer-term use.[1]
Although the general public typically uses the word "antihistamine" to describe drugs for treating allergies, physicians and scientists use the term to describe a class of drug that opposes the activity ofhistamine receptors in the body.[2] In this sense of the word, antihistamines are subclassified according to thehistamine receptor that they act upon. The two largest classes of antihistamines areH1-antihistamines andH2-antihistamines.
H1-antihistamines work by binding tohistamine H1 receptors inmast cells,smooth muscle, andendothelium in the body as well as in thetuberomammillary nucleus in the brain. Antihistamines that target thehistamine H1-receptor are used to treatallergic reactions in the nose (e.g., itching, runny nose, and sneezing). In addition, they may be used to treatinsomnia, motion sickness, orvertigo caused by problems with theinner ear. H2-antihistamines bind tohistamine H2 receptors in the uppergastrointestinal tract, primarily in thestomach. Antihistamines that target thehistamine H2-receptor are used to treatgastric acid conditions (e.g.,peptic ulcers andacid reflux). Other antihistamines also targetH3 receptors andH4 receptors.
Histamine receptors exhibitconstitutive activity, so antihistamines can function as either a neutralreceptor antagonist or aninverse agonist at histamine receptors.[2][3][4][5] Only a few currently marketed H1-antihistamines are known to function as antagonists.[2][5]
Histamine makes blood vessels more permeable (vascular permeability), causing fluid to escape fromcapillaries intotissues, which leads to the classicsymptoms of anallergic reaction—a runny nose and watery eyes. Histamine also promotesangiogenesis.[6]
Antihistamines suppress the histamine-inducedwheal response (swelling) andflare response (vasodilation) by blocking the binding of histamine to its receptors or reducing histamine receptor activity onnerves,vascular smooth muscle, glandular cells,endothelium, andmast cells. Antihistamines can also help correctEustachian Tube dysfunction, thereby helping correct problems such as muffled hearing, fullness in the ear and eventinnitus.[7]
Itching,sneezing, and inflammatory responses are suppressed by antihistamines that act onH1-receptors.[2][8] In 2014, antihistamines such asdesloratadine were found to be effective to complement standardized treatment ofacne due to theiranti-inflammatory properties and their ability to suppresssebum production.[9][10]
H1-antihistamines refer to compounds that inhibit the activity of theH1 receptor.[4][5] Since the H1 receptor exhibitsconstitutive activity, H1-antihistamines can be either neutralreceptor antagonists orinverse agonists.[4][5] 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 both block the binding of histamine, and reduce its constitutive activity, an effect which is opposite to histamine's.[4] Most antihistamines are inverse agonists at the H1 receptor, but it was previously thought that they were antagonists.[11]
Clinically, H1-antihistamines are used to treatallergic reactions andmast cell-related disorders.Sedation is a common side effect of H1-antihistamines that readily cross theblood–brain barrier; some of these drugs, such asdiphenhydramine anddoxylamine, may therefore be used to treatinsomnia. H1-antihistamines can also reduce inflammation, since the expression ofNF-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.[2]
A combination of these effects, and in some cases metabolic ones as well, lead to most first-generation antihistamines havinganalgesic-sparing (potentiating) effects onopioidanalgesics and to some extent with non-opioid ones as well. The most common antihistamines utilized for this purpose includehydroxyzine,promethazine (enzyme induction especially helps withcodeine and similarprodrug opioids),phenyltoloxamine,orphenadrine, andtripelennamine; some may also have intrinsic analgesic properties of their own, orphenadrine being an example.
Second-generation antihistamines cross theblood–brain barrier to a much lesser extent than the first-generation antihistamines. They minimize sedatory effects due to their focused effect on peripheral histamine receptors. However, upon high doses second-generation antihistamines will begin to act on the central nervous system and thus can induce drowsiness when ingested in higher quantity.
H2-antihistamines, like H1-antihistamines, exist asinverse agonists and neutralantagonists. They act onH2 histamine receptors found mainly in theparietal cells of thegastric mucosa, which are part of the endogenous signaling pathway forgastric 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 treatgastrointestinal conditions includingpeptic ulcers andgastroesophageal 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:
AnH3-antihistamine is a classification ofdrugs used to inhibit the action ofhistamine at theH3 receptor. H3 receptors are primarily found in the brain and are inhibitoryautoreceptors located on histaminergic nerve terminals, which modulate the release ofhistamine. Histamine release in the brain triggers secondary release of excitatory neurotransmitters such asglutamate andacetylcholine via stimulation of H1 receptors in thecerebral cortex. Consequently, unlike the H1-antihistamines which are sedating, H3-antihistamines havestimulant and cognition-modulating effects.
Examples of selective H3-antihistamines include:
H4-antihistamines inhibit the activity of theH4 receptor. Examples include:
| Receptor | Location | Mechanism of action | Function | Antagonists | Uses of antagonists |
|---|---|---|---|---|---|
| H1 | Throughout the body, especially in:[17]
| Gq |
| ||
| H2 |
| Gs ↑cAMP2+ |
| ||
| H3 |
| Gi |
| ||
| H4 | Gi |
| As of July 2021[update], no clinical uses exist. Potential uses include:[20] |
Inhibit the action ofhistidine decarboxylase:
Mast cell stabilizers are drugs which prevent mast celldegranulation. Examples include:
The first H1 receptor antagonists were discovered in the 1930s and were marketed in the 1940s.[22]Piperoxan was discovered in 1933 and was the first compound with antihistamine effects to be identified.[22] Piperoxan and itsanalogues were tootoxic to be used in humans.[22]Phenbenzamine (Antergan) was the first clinically useful antihistamine and was introduced for medical use in 1942.[22] Subsequently, many other antihistamines were developed and marketed.[22]Diphenhydramine (Benadryl) was synthesized in 1943,tripelennamine (Pyribenzamine) was patented in 1946, andpromethazine (Phenergan) was synthesized in 1947 and launched in 1949.[22][23][24] By 1950, at least 20 antihistamines had been marketed.[25]Chlorphenamine (Piriton), a less sedating antihistamine, was synthesized in 1951, andhydroxyzine (Atarax, Vistaril), an antihistamine used specifically as a sedative and tranquilizer, was developed in 1956.[22][26] The first non-sedating antihistamine wasterfenadine (Seldane) and was developed in 1973.[22][27] Subsequently, other non-sedating antihistamines likeloratadine (Claritin),cetirizine (Zyrtec), andfexofenadine (Allegra) were developed and introduced.[22]
The introduction of the first-generation antihistamines marked the beginning of medical treatment of nasal allergies.[28] Research into these drugs led to the discovery that they wereH1 receptor antagonists and also to the development ofH2 receptor antagonists, where H1-antihistamines affected the nose and the H2-antihistamines affected the stomach.[29] This history has led to contemporary research into drugs which areH3 receptor antagonists and which affect theH4 receptor antagonists.[29] Most people who use an H1 receptor antagonist to treat allergies use a second-generation drug.[1]
The United States government removed two second generation antihistamines,terfenadine andastemizole, from the market based on evidence that they could cause heart problems.[1]
Not much published research exists which compares the efficacy and safety of the various antihistamines available.[1] The research which does exist is mostly short-term studies or studies which look at too few people to make general assumptions.[1] Another gap in the research is in information reporting the health effects for individuals with long-term allergies who take antihistamines for a long period of time.[1] Newer antihistamines have been demonstrated to be effective in treating hives.[1] However, there is no research comparing the relative efficacy of these drugs.[1]
In 2020, the UKNational Health Service wrote that "[m]ost people can safely take antihistamines" but that "[s]ome antihistamines may not be suitable" for young children, the pregnant or breastfeeding, for those taking other medicines, or people with conditions "such as heart disease, liver disease, kidney disease or epilepsy".[30]
Most studies of antihistamines reported on people who are younger, so the effects on people over age 65 are not as well understood.[1] Older people are more likely to experience drowsiness from antihistamine use than younger people.[1] Continuous and/or cumulative use ofanticholinergic medications, including first-generation antihistamines, is associated with higher risk for cognitive decline and dementia in older people.[31][32]
Also, most of the research has been on caucasians and other ethnic groups are not as represented in the research.[1] The evidence does not report how antihistamines affect women differently than men.[1] Different studies have reported on antihistamine use in children, with various studies finding evidence that certain antihistamines could be used by children 2 years of age, and other drugs being safer for younger or older children.[1]
Research regarding the effects of commonly used medications upon certain cancer therapies has suggested that when consumed in conjunction with immune checkpoint inhibitors some may influence the response of subjects to that particular treatment whose T-cell functions were failing in anti-tumor activity. Upon study of records in mouse studies associated with 40 common medications ranging from antibiotics, antihistamines, aspirin, and hydrocortisone, that for subjects with melanoma and lung cancers, fexofenadine, one of three medications, along with loratadine, and cetirizine, that target histamine receptor H1 (HRH1), demonstrated significantly higher survival rates and had experienced restored T-cell anti-tumor activity, ultimately inhibiting tumor growth in the subject animals.[33] Such results encourage further study in order to see whether results in humans is similar in combating resistance to immunotherapy.
The H1-receptor is a transmembrane protein belonging to the G-protein coupled receptor family. Signal transduction from the extracellular to the intracellular environment occurs as the GCPR becomes activated after binding of a specific ligand or agonist. A subunit of the G-protein subsequently dissociates and affects intracellular messaging including downstream signaling accomplished through various intermediaries such as cyclic AMP, cyclic GMP, calcium, and nuclear factor kappa B (NF-κB), a ubiquitous transcription factor thought to play an important role in immune-cell chemotaxis, proinflammatory cytokine production, expression of cell adhesion molecules, and other allergic and inflammatory conditions.1,8,12,30–32 ... For example, the H1-receptor promotes NF-κB in both a constitutive and agonist-dependent manner and all clinically available H1-antihistamines inhibit constitutive H1-receptor-mediated NF-κB production ...
Importantly, because antihistamines can theoretically behave as inverse agonists or neutral antagonists, they are more properly described as H1-antihistamines rather than H1-receptor antagonists.15
