Antihistamine

Antihistamines are drugs which treat

allergic rhinitis and other allergies.[1]
Typically people take antihistamines as
an inexpensive, generic, over-the-counter
drug that can provide relief from nasal
congestion, sneezing, or hives caused by
pollen, dust mites, or animal 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, including asthma,
sinusitis, and lower respiratory tract
infection.[1] Consultation of a medical
professional is recommended for those
who intend to take antihistamines for
longer-term use.[1]
 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
MeSH D006633

In Wikidata

Although people typically 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.[2] 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.

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. Antihistamines that
target the histamine H1-receptor are used
to treat allergic reactions in the nose
(e.g., itching, runny nose, and sneezing).
In addition, they may be used to treat
insomnia, motion sickness, or vertigo
caused by problems with the inner ear.
H2-antihistamines bind to histamine H2
receptors in the upper gastrointestinal
tract, primarily in the stomach.
Antihistamines that target the histamine
H2-receptor are used to treat gastric acid
conditions (e.g., peptic ulcers and acid
reflux).
Histamine receptors exhibit constitutive
activity, so antihistamines can function
as either a neutral receptor antagonist or
an inverse agonist at histamine
receptors.[2][3][4][5] Only a few currently
marketed H1-antihistamines are known
to function as inverse agonists.[2][5]

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.[6]
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.[2][7] 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.[8][9]

Types
H1-antihistamines

H1-antihistamines refer to compounds

that inhibit the activity of the H1
receptor.[4][5] Since the H1 receptor
exhibits constitutive activity, H1-
antihistamines can be either neutral
receptor antagonists or inverse
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 reduce its activity, an
effect which is opposite to histamine's.[4]

The vast majority of marketed H1-

antihistamines are receptor antagonists.
Only a minority of marketed compounds
are inverse agonists at the receptor.[2][5]
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, may
therefore be 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.[2]

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 common antihistamines utilized for
this 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 example.

Second-generation antihistamines cross

the blood–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. Additionally, some
second-generation antihistamines,
notably cetirizine, can interact with CNS
psychoactive drugs such as bupropion
and benzodiazepines.[10]

H1 antagonists

Examples of H1 antagonists include:

Acrivastine (see Benadryl entry in this

section)
Azelastine
Benadryl is a brand name for different
H1 antagonist antihistamine
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
https://web.archive.org/web/2017020
1041252/http://www.benadryl.ca/adult
-allergy-medicine/benadryl-caplets ).
Bilastine
Bromodiphenhydramine
Brompheniramine
Buclizine
Carbinoxamine
Cetirizine (Zyrtec)
Chlorodiphenhydramine
Chlorpheniramine
Clemastine
Cyclizine
Cyproheptadine
Desloratadine (Aerius)
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/Telfast)
Hydroxyzine (Vistaril)
Levocabastine (Livostin/Livocab)
Levocetirizine (Xyzal)
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 (Alergoliber)
Tripelennamine
Triprolidine

H1 inverse agonists

The H1 receptor inverse agonists

include:[2][5]

Levocetirizine (does not cross the

blood–brain barrier)
 Desloratadine (does not cross the
blood–brain barrier)
Pyrilamine (crosses the blood–brain
barrier; produces drowsiness)

H2-antihistamines

H2-antihistamines, like H1-antihistamines,

exist 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

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,[11]
ABT-239[12]
Ciproxifan,[13]
Conessine
A-349,821.[14]
Thioperamide

H4-antihistamines
H4-antihistamines inhibit the activity of
the H4 receptor.

Examples:

Thioperamide
JNJ 7777120
VUF-6002

Atypical antihistamines
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
β-agonists

History
Currently most people who use an
antihistamine to treat allergies use a
second-generation drug.[1]

The first generation of antihistamine

drugs became available in the 1930s.[15]
This marked the beginning of medical
treatment of nasal allergies.[15] Research
into these drugs led to the discovery that
they were H1 antagonists and also to the
development of H2 antagonists, where
H1 antihistamines affected the nose and
the H2 antihistamines affected the
stomach.[16] This history has led to
contemporary research into drugs which
are H3 receptor antagonist and which
affect the Histamine H4 receptor.[16]

Society and culture

Antihistamines can vary greatly in cost.[1]
Some patients consult with their doctor
about drug prices to make a decision
about which antihistamine to choose.[1]
Many antihistamines are older and
available in generic form.[1] Others are
newer, still under patent, and generally
expensive.[1] The newer drugs are not
necessarily safer or more effective.[1]
Because so many antihistamines are
available, patients can have
conversations with their health care
provider to choose the right drug for
them.[1]

The United States government removed

two second generation antihistamines,
terfenadine and astemizole, from the
market based on evidence that they
could cause heart problems.[1]
Research
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 to take antihistamines for
a long period of time.[1] Newer
antihistamines have been demonstrated
to be effective in treating hives.[1]
However, there is not research
comparing the relative efficacy of these
drugs.[1]

Special populations
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]
Also, most of the research has been on
white people and other ethnicities 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]

See also
Antileukotriene
Immunotherapy

References
1. Consumer Reports (2013), Using
Antihistamines to Treat Allergies,
Hay Fever, & Hives - Comparing
Effectiveness, Safety, and Price
(PDF), Yonkers, New York:
 Consumer Reports, archived from
the original (PDF) on 17 May 2017,
retrieved 29 June 2017
2. Canonica GW, Blaiss M (2011).
"Antihistaminic, anti-inflammatory,
and antiallergic properties of the
nonsedating second-generation
antihistamine desloratadine: a
review of the evidence" . World
Allergy Organ J. 4 (2): 47–53.
doi:10.1097/WOX.0b013e3182093
e19 . PMC 3500039 .
PMID 23268457 . "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"
3. Panula P, Chazot PL, Cowart M, et
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Basic and Clinical Pharmacology.
 XCVIII. Histamine Receptors" .
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(April 2002). "H1-antihistamines:
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6. Norrby K (1995). "Evidence of a dual
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3 . PMID 9042073 .
8. Lee HE, Chang IK, Lee Y, Kim CD,
Seo YJ, Lee JH, Im M (2014). "Effect
 of antihistamine as an adjuvant
treatment of isotretinoin in acne: a
randomized, controlled comparative
study". J Eur Acad Dermatol
Venereol. 28 (12): 1654–60.
doi:10.1111/jdv.12403 .
PMID 25081735 .
9. Layton AM (2016). "Top Ten List of
Clinical Pearls in the Treatment of
Acne Vulgaris" . Dermatol Clin. 34
(2): 147–57.
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PMID 27015774 .
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drugs.com. Retrieved 28 January
2017.
11. Yoneyama H, et al. (March 2008).
"Efficient approaches to S-alkyl-N-
alkylisothioureas: syntheses of
histamine H3 antagonist
clobenpropit and its analogues".
The Journal of Organic Chemistry.
73 (6): 2096–104.
doi:10.1021/jo702181x .
PMID 18278935 .
12. Fox GB, Esbenshade TA, Pan JB,
Radek RJ, Krueger KM, Yao BB,
Browman KE, Buckley MJ, Ballard
ME, Komater VA, Miner H, Zhang M,
Faghih R, Rueter LE, Bitner RS,
Drescher KU, Wetter J, Marsh K,
Lemaire M, Porsolt RD, Bennani YL,
Sullivan JP, Cowart MD, Decker MW,
 Hancock AA (April 2005).
"Pharmacological properties of ABT-
239 [4-(2-{2-[(2R)-2-
Methylpyrrolidinyl]ethyl}-
benzofuran-5-yl)benzonitrile]: II.
Neurophysiological characterization
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PMID 15608077 .
13. Ligneau X, Lin J, Vanni-Mercier G,
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 Schwartz J (November 1998).
"Neurochemical and behavioral
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14. Esbenshade TA, Fox GB, Krueger
KM, Baranowski JL, Miller TR, Kang
CH, Denny LI, Witte DG, Yao BB, Pan
JB, Faghih R, Bennani YL, Williams
M, Hancock AA (September 2004).
"Pharmacological and behavioral
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 doi:10.1016/j.bcp.2004.05.048 .
PMID 15294456 .
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PMID 25582156 .
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PMID 27119574 .

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

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title=Antihistamine&oldid=898427941"

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