Antihistamines are drugs which treat allergic rhinitis and other
allergies. Antihistamines can give relief when a person has nasal
congestion, sneezing, or hives because of pollen, dust mites, or
animal allergy. Typically people take antihistamines as an
inexpensive, generic, over-the-counter drug with few side effects.
As an alternative to taking an antihistamine, people who suffer from
allergies can instead avoid the substance which irritates them.
Antihistamines are usually for short-term treatment. Chronic
allergies increase the risk of health problems which antihistamines
might not treat, including asthma, sinusitis, and lower respiratory
tract infection. Doctors recommend that people talk to them before
any longer term use of antihistamines.
Although typical people use the word “antihistamine” to describe
drugs for treating allergies, doctors and scientists use the term to
describe a class of drug that opposes the activity of histamine
receptors in the body. In this sense of the word, 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 receptors. Only a few currently
marketed H1-antihistamines are known to function as inverse
1 Medical uses
2.1.1 H1 antagonists
2.1.2 H1 inverse agonists
4 Related agents
Histidine decarboxylase inhibitors
Mast cell stabilizers
6 Society and culture
9 See also
11 External links
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
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.
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.
A combination of these effects, and in some cases metabolic ones as
well, lead to most first-generation antihistamines having
analgesic-sparing (potentiating) effects on opioid analgesics and to
some extent with non-opioid ones as well. The most commonly used for
the purpose include hydroxyzine, promethazine (enzyme induction
especially helps with codeine and similar prodrug opioids),
phenyltoloxamine, orphenadrine, and tripelennamine; some may also have
intrinsic analgesic properties of their own, orphenadrine being an
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
drowsiness through acting on the central nervous system. Some
second-generation antihistamines, notably cetirizine, can interact
with CNS psychoactive drugs such as bupropion and benzodiazepines.
H1 antagonists include:
Benadryl entry in this section)
Benadryl is a brand name for different
H1 antagonist anitihistamine
preparations in different regions: acrivastine is the active component
Benadryl Allergy Relief and cetirizine of
Benadryl One a Day Relief
in the UK;
Benadryl is diphenhydramine in the US and Canada (see
Dimenhydrinate (most commonly used as an antiemetic)
Benadryl entry in this section)
Doxylamine (most commonly used as an over-the-counter drug sedative)
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)
Quetiapine (antipsychotic; trade name Seroquel)
H1 inverse agonists
The H1 receptor inverse agonists include:
Cetirizine (does not cross the blood–brain barrier)
Desloratadine (does not cross the blood–brain barrier)
Pyrilamine (crosses the blood–brain barrier; produces drowsiness)
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.
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.
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 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:
Histidine decarboxylase inhibitors
Inhibit the action of histidine decarboxylase:
Mast cell stabilizers
Mast cell stabilizer
Mast cell stabilizers are drugs which prevent mast cell degranulation.
Currently most people who use an antihistamine to treat allergies use
a second generation drug.
The first generation of antihistamine drugs became available in the
1930s. This marked the beginning of medical treatment of nasal
allergies. Research into these drugs led to the discovery that
H1 antagonists and also to the development of H2
antagonists, where H1 antihistamines affected the nose and the H2
antihistamines affected the stomach. This history has led to
contemporary research into drugs which are
H3 receptor antagonist and
which affect the
Histamine H4 receptor.
Society and culture
Antihistamines can vary greatly in cost. Some patients consult with
their doctor about drug prices to make a decision about which
antihistamine to choose. Many antihistamines are older and
available in generic form. Others are newer, still under patent,
and generally expensive. The newer drugs are not necessarily safer
or more effective. Because so many antihistamines are available,
patients can have conversations with their health care provider to
choose the right drug for them.
The United States government removed two second generation
antihistamines, terfenadine and astemizole, from the market based on
evidence that they could cause heart problems.
Not much published research exists which compares the efficacy and
safety of the various antihistamines available. The research which
does exist are mostly short term studies or studies which look at too
few people to make general assumptions. Another gap in the research
is in information reporting the health effects for individuals with
long term allergies to take antihistamines for a long period of
time. Newer antihistamines have been demonstrated to be effective
in treating hives. However, there is not research comparing the
relative efficacy of these drugs.
Most studies of antihistamines reported on people who are younger, so
the effects on people over age 65 are not as well understood. Older
people are more likely to experience drowsiness from antihistamine use
than younger people. Also, most of the research has been on white
people and other ethnicities are not as represented in the
research. The evidence does not report how antihistamines affect
women differently than men. 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.
^ a b c d e f g h i j k l m n o p q r s t u v w x y Consumer Reports
(2013), Using Antihistamines to Treat Allergies, Hay Fever, &
Hives - Comparing Effectiveness, Safety, and Price (PDF), Yonkers, New
York: Consumer Reports
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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
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NF-κB in both a constitutive and agonist-dependent manner
and all clinically available H1-antihistamines inhibit constitutive
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
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Histamine antagonist at the US National Library of Medicine Medical
Subject Headings (MeSH)
Antihistamine information at Allergy UK
Dibenzocycloheptenes: Antidepressants (e.g., amitriptyline)
Others: Antidepressants (e.g., doxepin, mirtazapine, trimipramine)
Phenylpiperazines: Antidepressants (e.g., trazodone)
For topical use
Histamine receptor modulators
Antagonists: First-generation: 4-Methyldiphenhydramine
Others: Atypical antipsychotics (e.g., aripiprazole, asenapine,
brexpiprazole, clozapine, iloperidone, olanzapine, paliperidone,
quetiapine, risperidone, RP-5063, ziprasidone, zotepine)
Phenylpiperazine antidepressants (e.g., hydroxynefazodone, nefazodone,
Tetracyclic antidepressants (e.g., amoxapine, loxapine, maprotiline,
mianserin, mirtazapine, oxaprotiline)
Tricyclic antidepressants (e.g., amitriptyline, butriptyline,
clomipramine, desipramine, dosulepin (dothiepin), doxepin, imipramine,
iprindole, lofepramine, nortriptyline, protriptyline, trimipramine)
Typical antipsychotics (e.g., chlorpromazine, flupenthixol,
fluphenazine, loxapine, perphenazine, prochlorperazine, thioridazine,
See also: Receptor/signaling modulators • Monoamine metabolism
modulators • Monoamine reuptake inhibitors
♦ Enzyme: Inducer
♦ Ion channel: Opener
♦ Receptor: Agonist
Positive allosteric modulator (PAM)
Negative allosteric modulator (NAM)
♦ Transporter [
Reuptake vs Efflux]: Enhancer (RE)
♦ Miscellaneous: Precursor
Calcium channel blocker
Calcium channel blocker (CCB)
Potassium channel blocker
Potassium channel blocker (PCB)
Sodium channel blocker
Sodium channel blocker (SCB)
Potassium channel opener (PCO)
Adrenergic receptor agonist (α
Adrenergic receptor antagonist (α (1
Norepinephrine reuptake inhibitor
Norepinephrine reuptake inhibitor (NRI)
Dopamine receptor agonist
Dopamine receptor antagonist
Dopamine reuptake inhibitor
Dopamine reuptake inhibitor (DRI)
Histamine receptor agonist
Histamine receptor antagonist (H1
Serotonin receptor agonist
Serotonin receptor antagonist (5-HT3)
Serotonin reuptake inhibitor
Serotonin reuptake inhibitor (SRI)
GABA receptor agonist
GABA receptor antagonist
GABA reuptake inhibitor
GABA reuptake inhibitor (GRI)
Glutamate receptor agonist (AMPA)
Glutamate receptor antagonist (NMDA)
Glutamate reuptake inhibitor
Acetylcholine receptor agonist (Muscarinic
Acetylcholine receptor antagonist (Muscarinic
Cannabinoid receptor agonist
Cannabinoid receptor antagonist
Endocannabinoid enhancer (eCBE)
Endocannabinoid reuptake inhibitor (eCBRI)
Opioid receptor agonist
Opioid receptor antagonist
Adenosine reuptake inhibitor
Adenosine reuptake inhibitor (AdoRI)
Angiotensin II receptor antagonist
Endothelin receptor antagonist
NK1 receptor antagonist
Vasopressin receptor antagonist