An antihistamine is a drug which serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions, through action at the histamine receptor. Only agents where the main therapeutic effect is mediated by negative modulation of histamine receptors are termed antihistamines - other agents may have antihistaminergic action but are not true antihistamines. For other meanings, see Drug (disambiguation). ... This article or section does not cite any references or sources. ... This article needs additional references or sources for verification. ... The histamine receptors are a class of G-protein coupled receptors with histamine as their endogenous ligand. ...

In common use, the term antihistamine refers only to H₁-receptor antagonists, also known as H₁-antihistamines. It has been discovered that these H₁-antihistamines are actually inverse agonists at the histamine H₁-receptor, rather than antagonists per se. (Leurs, Church & Taglialatela, 2002) In pharmacology, an inverse agonist is an agent which binds to the same receptor binding-site as an agonist for that receptor but exerts the opposite pharmacological effect. ... Antagonists In medicine and biology, a receptor antagonist is a ligand that inhibits the function of an agonist and inverse agonist for a specific receptor. ...

Pharmacology

In allergic reactions an allergen (a type of antigen) interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. An allergen is any substance (antigen), most often eaten or inhaled, that is recognized by the immune system and causes an allergic reaction. ... An antigen is a molecule that stimulates an immune response. ... Each antibody binds to a specific antigen; an interaction similar to a lock and key. ... Mast cells A mast cell (or mastocyte) is a resident cell of areolar connective tissue (loose connective tissue) that contains many granules rich in histamine and heparin. ... Categories: Wikipedia cleanup | Biology stubs | Blood and immune system cells ... The degranulation process in a Mast cell. ... The histamine receptors are a class of G-protein coupled receptors with histamine as their endogenous ligand. ...

Histamine, acting on H₁-receptors, produces pruritus, vasodilatation, hypotension, flushing, headache, tachycardia, bronchoconstriction, increases vascular permeability, potentiates pain, and more. (Simons, 2004) An itch (Latin: pruritus) is a sensation felt on an area of skin that causes a person or animal to desire to scratch that area. ... The blood vessels are part of the circulatory system and function to transport blood throughout the body. ... In physiology and medicine, hypotension refers to an abnormally low blood pressure. ... For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. ... A headache (cephalalgia in medical terminology) is a condition of pain in the head; sometimes neck or upper back pain may also be interpreted as a headache. ... This article or section does not cite any references or sources. ... Bronchoconstriction is the constriction of the airways in the lungs due to the tighting of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. ... Vascular permeability characterizes the capacity of a blood vessel wall to pass through small molecules (ions, water, nutrients) or even whole cells (lymphocytes on their way to the site of inflammation). ... “Hurting” redirects here. ...

While H₁-antihistamines help against these effects, they only work if taken before contact with the allergen. In severe allergies, such as anaphylaxis or angioedema, these effects may be so severe as to be life-threatening. Epinephrine, often in the form of an autoinjector (Epi-pen), is required by people with such hypersensitivities. Anaphylaxis is an acute systemic (multi-system) and severe Type I Hypersensitivity allergic reaction. ... Angioedema (BE: angiooedema), also known by its eponym Quinckes edema, is the rapid swelling (edema) of the skin, mucosa and submucosal tissues. ... Adrenaline redirects here. ... A 0. ...

Clinical use of antihistamines

Indications

H₁-antihistamines are clinically used in the treatment of histamine-mediated allergic conditions. Specifically, these indications may include: (Rossi, 2004)

• Allergic rhinitis
• Allergic conjunctivitis
• Allergic dermatological conditions (contact dermatitis)
• Urticaria
• Angioedema
• Pruritus (atopic dermatitis, insect bites)
• Anaphylactic or anaphylactoid reactions - adjunct only
• Nausea and vomiting (first-generation H₁-antihistamines)
• Sedation (first-generation H₁-antihistamines)

Antihistamines can be administered topically (through the skin, nose, or eyes) or systemically, based on the nature of the allergic condition. Rhinitis is the medical term describing irritation and inflammation of the nose. ... In zootomy and dermatology, skin is the largest organ of the integumentary system made up of multiple layers of epithelial tissues that guard underlying muscles and organs. ... Contact dermatitis is a term for a skin reaction resulting from exposure to allergens or irritants. ... Angioedema (BE: angiooedema), also known by its eponym Quinckes edema, is the rapid swelling (edema) of the skin, mucosa and submucosal tissues. ... An itch (Latin: pruritus) is a sensation felt on an area of skin that makes a person or animal want to scratch it. ... Anaphylaxis is an acute systemic (multi-system) and severe Type I Hypersensitivity allergic reaction. ... In zootomy and dermatology, skin is the largest organ of the integumentary system made up of multiple layers of epithelial tissues that guard underlying muscles and organs. ... For the article about nose in humans, see human nose Human nose in profile Elephants have prehensile noses Dogs have very sensitive noses Anatomically, a nose is a protuberance in vertebrates that houses the nostrils, or nares, which admit and expel air for respiration in conjunction with the mouth. ... // A human eye. ...

The authors of the American College of Chest Physicians Updates on Cough Guidelines (2006) recommend that for cough associated with the common cold, first-generation antihistamine-decongestants are more effective than newer, nonsedating antihistamines. First generation antihistamines include Diphenhydramine (Benadryl); Carbinoxamine (Clistin); Clemastine (Tavist);Chlorpheniramine (Chlor-Trimeton)and Brompheniramine (Dimetane). Diphenhydramine hydrochloride (trade name Benadryl, as produced by Pfizer, or Dimedrol outside the U.S.) is an over-the-counter (OTC) antihistamine and sedative. ...

Adverse drug reactions

Adverse drug reactions are most commonly associated with the first-generation H₁-antihistamines. This is due to their relative lack of selectivity for the H₁-receptor. An adverse drug reaction (abbreviated ADR) is a term to describe the unwanted, negative consequences sometimes associated with the use of medications. ...

The most common adverse effect is sedation; this "side effect" is utilized in many OTC sleeping-aid preparations. Other common adverse effects in first-generation H₁-antihistamines include: dizziness, tinnitus, blurred vision, euphoria, uncoordination, anxiety, insomnia, tremor, nausea and vomiting, constipation, diarrhoea, dry mouth, and dry cough. Infrequent adverse effects include: urinary retention, palpitations, hypotension, headache, hallucination, and psychosis. (Rossi, 2004) Over-the-counter substances, also abbreviated OTC, are drugs and other medical remedies that may be sold without a prescription and without a visit to a medical professional, in contrast to prescription only medicines (POM). ... Tinnitus (IPA pronunciation: or ,[1] from the Latin word for ringing[2]) is the perception of sound in the human ear in the absence of corresponding external sound(s). ... Euphoria is a medically recognized emotional state related to happiness. ... This article includes a list of works cited or a list of external links, but its sources remain unclear because it lacks in-text citations. ... This article is about the sleeping disorder. ... For the Beck song, see Nausea (song). ... Constipation or irregularity, is a condition of the digestive system where a person (or animal) experiences hard feces that are difficult to egest; it may be extremely painful, and in severe cases (fecal impaction) lead to symptoms of bowel obstruction. ... Diarrhoea is the correct way to spell the word Diarrhoea. ... This article does not cite any references or sources. ... In physiology and medicine, hypotension refers to an abnormally low blood pressure. ... A headache (cephalalgia in medical terminology) is a condition of pain in the head; sometimes neck or upper back pain may also be interpreted as a headache. ... A hallucination is a sensory perception experienced in the absence of an external stimulus, as distinct from an illusion, which is a misperception of an external stimulus. ... Psychosis is a generic psychiatric term for a mental state often described as involving a loss of contact with reality. Stedmans Medical Dictionary defines psychosis as a severe mental disorder, with or without organic damage, characterized by derangement of personality and loss of contact with reality and causing deterioration...

The newer second-generation H₁-antihistamines are far more selective for peripheral histamine H₁-receptors and, correspondingly, have a far improved tolerability profile compared to the first-generation agents. The most common adverse effects noted for second-generation agents include: drowsiness, fatigue, headache, nausea and dry mouth. (Rossi, 2004)

First-generation H₁-receptor antagonists

These are the oldest antihistaminergic drugs and are relatively inexpensive and widely available. They are effective in the relief of allergic symptoms, but are typically moderately to highly potent muscarinic acetylcholine receptor-antagonists (anticholinergic) agents as well. These agents also commonly have action at α-adrenergic receptors and/or 5-HT receptors. This lack of receptor-selectivity is the basis of the poor tolerability-profile of some of these agents, especially compared with the second-generation H₁-antihistamines. Patient response and occurrence of adverse drug reactions vary greatly between classes and between agents within classes. An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of the neurotransmitter acetylcholine. ... An anticholinergic agent is a member of a class of pharmaceutical compounds which serve to reduce the effects mediated by acetylcholine in the central nervous system and peripheral nervous system. ... Epinephrine Norepinephrine The adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of the catecholamines. ... In the field of neurochemistry, 5-HT receptors are receptors for the neurotransmitter and peripheral signal mediator serotonin, also known as 5-hydroxytryptamine or 5-HT. 5-HT receptors are located on the cell membrane of nerve cells and other cell types in animals and mediate the effects of serotonin...

The first H₁-antihistamine discovered was piperoxan, by Jeff Forneau and Daniel Bovet (1933) in their efforts to develop a guinea pig animal-model for anaphylaxis at Ryerson University. Bovet went on to win the 1957 Nobel Prize in Physiology or Medicine for his contribution. Following their discovery, the first-generation H₁-antihistamines were developed in the following decades. They can be classified on the basis of chemical structure, and agents within these groups have similar properties. Daniel Bovet (March 23, 1907 – April 8, 1992) was a Swiss-born Italian pharmacologist who won the 1957 Nobel Prize in Physiology or Medicine for his discovery of drugs that block the actions of specific neurotransmitters. ... Binomial name Cavia porcellus (Linnaeus, 1758) Guinea pigs (also called cavies) are rodents belonging to the family Caviidae and the genus Cavia, originally indigenous to the Andes. ... Anaphylaxis is an acute systemic (multi-system) and severe Type I Hypersensitivity allergic reaction. ... Ryerson University is a public university located in downtown Toronto, Canada. ... List of Nobel Prize laureates in Physiology or Medicine from 1901 to the present day. ...

Ethylenediamines

Ethylenediamines were the first group of clinically-effective H₁-antihistamines developed.

• Mepyramine (pyrilamine)
• Antazoline

Mepyramine[1] is a first generation antihistamine. ...

Ethanolamines

Diphenhydramine was the prototypical agent in this group. Significant anticholinergic adverse effects, as well as sedation, are observed in this group but the incidence of gastrointestnal adverse effects is relatively low. (Nelson, 2002; Rossi, 2004) An anticholinergic agent is a member of a class of pharmaceutical compounds which serve to reduce the effects mediated by acetylcholine in the central nervous system and peripheral nervous system. ...

• Diphenhydramine
• Carbinoxamine
• Doxylamine
• Clemastine
• Dimenhydrinate

Diphenhydramine hydrochloride (trade name Benadryl, as produced by Pfizer, or Dimedrol outside the U.S.) is an over-the-counter (OTC) antihistamine and sedative. ... Carbinoxamine is an antihistamine. ... This article or section may be confusing or unclear for some readers, and should be edited to rectify this. ... Clemastine is an over-the-counter antihistamine sold in the United States under the name Tavist. ... Dramamine redirects here. ...

Alkylamines

The isomerism is a significant factor in the activity of the agents in this group. E-triprolidine, for example, is 1000-fold more potent than Z-triprolidine. This difference relates to the positioning and fit of the molecules in the histamine H₁-receptor binding site. (Nelson, 2002) Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse effects, but relatively greater incidence of paradoxical CNS stimulation. (Rossi, 2004) In chemistry, isomers are molecules with the same chemical formula and often with the same kinds of chemical bonds between atoms, but in which the atoms are arranged differently (analogous to a chemical anagram). ... A diagram showing the CNS: 1. ...

• Pheniramine
• Chlorphenamine (chlorpheniramine)
• Dexchlorphenamine
• Brompheniramine
• Triprolidine

Pheniramine maleate is an antihistamine used to treat allergic conditions such as hay fever or urticaria. ... Chlorphenamine (INN) or chlorpheniramine (USAN, former BAN), commonly marketed as its salt chlorphenamine maleate (CPM), is first-generation antihistamine used in the prevention of the symptoms of allergic conditions such as rhinitis and urticaria. ... Categories: Stub | Antihistamines ... Triprolidine hydrochloride is an over-the-counter antihistamine. ...

Piperazines

These compounds are structurally-related to the ethylenediamines and the ethanolamines; and produce significant anticholinergic adverse effects. Compounds from this group are often used for motion sickness, vertigo, nausea and vomiting. The second-generation H₁-antihistamine cetirizine also belongs to this chemical group. (Nelson, 2002) An anticholinergic agent is a member of a class of pharmaceutical compounds which serve to reduce the effects mediated by acetylcholine in the central nervous system and peripheral nervous system. ... Cetirizine hydrochloride (IPA sÉ›.ˈtɪɹ.ɪ.ËŒzin) is a major metabolite of hydroxyzine, and a racemic selective H1 receptor antagonist used in the treatment of allergies, hay fever, angioedema, and urticaria. ...

• Cyclizine
• Chlorcyclizine
• Hydroxyzine
• Meclizine

Cyclizine is an antihistamine drug used to treat nausea, vomiting and dizziness associated with motion sickness, vertigo and post-operative following administration of general anaesthesia and opioids. ... This article belongs in one or more categories. ... Hydroxyzine is a piperazine derivative that is used as an antihistamine (especially for itches), anti-emetic (nausea reducing), and anxiolytic (anxiety reducing) drug. ... Meclizine is an antihistamine, considered to be an antiemetic. ...

Tricyclics

These compounds differ from the phenothiazine antipsychotics in the ring-substitution and chain characteristics. (Nelson, 2002) They are also structurally-related to the tricyclic antidepressants, explaining the antihistaminergic adverse effects of those two drug classes and also the poor tolerability profile of tricyclic H₁-antihistamines. The second-generation H₁-antihistamine loratadine was derived from compounds in this group. Phenothiazines are the largest of the 5 main classes of antipsychotic drugs. ... The term antipsychotic is applied to a group of drugs used to treat psychosis. ... Chemical structure of the tricyclic antidepressant amitriptyline. ...

• Promethazine
• Alimemazine (trimeprazine)
• Cyproheptadine
• Azatadine
• Ketotifen

Promethazine is a first-generation H1 receptor antagonist antihistamine and antiemetic medication. ... Periactin® (cyproheptadine hydrochloride) is an antihistaminic and antiserotonergic agent. ... Azatadine is an antihistamine. ... Ketotifen fumarate (Zaditor®) is an H1-antihistamine available in two forms. ...

Common structural features of classical antihistamine

• Two aromatic rings, connected to a central carbon, nitrogen or CO
• Spacer between the central X and the amine, usually 2-3 carbons in length, linear, ring, branched, saturated or unsaturated
• Amine is substituted with small alkyl groups eg CH3

X = N, R1 = R2 = small alkyl groups
X = C
X = CO

• Chirality at X can increase both the potency and selectivity for H1-receptors
• For maximum potency, the two aromatic rings should be orientated in different planes.
  • for example, tricyclic ring system is slightly puckered and the two aromatic rings lie in different geometrical planes, giving the drug a very high potency.

Second-generation H₁-receptor antagonists

These are newer drugs that are much more selective for peripheral H₁ receptors in preference to the central nervous system histaminergic and cholinergic receptors. This selectivity significantly reduces the occurrence of adverse drug reactions compared with first-generation agents, while still providing effective relief of allergic conditions. A diagram showing the CNS: 1. ...

Systemic

• Acrivastine
• Astemizole
• Cetirizine
• Loratadine
• Mizolastine
• Terfenadine (withdrawn from most markets due to risk of cardiac arrhythmias and replaced with fexofenadine)

Acrivastine is a medication used for the treatment of allergies and hay fever. ... Astemizole is a second generation antihistamine that has a long duration of action. ... Cetirizine hydrochloride (IPA sɛ.ˈtɪɹ.ɪ.ˌzin) is a major metabolite of hydroxyzine, and a racemic selective H1 receptor antagonist used in the treatment of allergies, hay fever, angioedema, and urticaria. ... Loratadine is a drug used to treat allergies. ... Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. ... Cardiac arrhythmia is a group of conditions in which the electrical activity of the heart is irregular or is faster or slower than normal. ... Fexofenadine hydrochloride (brand names include Allegra® and Telfast®) is an antihistamine drug used in the treatment of hayfever and similar allergy symptoms. ...

Topical

• Azelastine
• Levocabastine
• Olopatadine

Azelastine hydrochloride is an antihistamine and mast cell stabilizer available as a nasal spray (Astelin®) for hay fever and as eye drops (Optilar®) for allergic conjunctivitis. ... Olopatadine hydrochloride is an antihistamine and mast cell stabilizer, usually sold as a prescription eye drop (0. ...

Common structural features of non-sedating antihistamines

Structure of these drugs varies from case to case. There is no common structural feature for the second generation H1-receptor antagonists.

Third-generation H₁-receptor antagonists

These are the active enantiomer (levocetirizine) or metabolite (desloratadine & fexofenadine) derivatives of second-generation drugs intended to have increased efficacy with fewer adverse drug reactions. Indeed, fexofenadine is associated with a decreased risk of cardiac arrhythmia compared to terfenadine. However, there is little evidence for any advantage of levocetirizine or desloratadine, compared to cetirizine or loratadine respectively. In chemistry, enantiomers are stereoisomers that are mirror images of each other. ... A metabolite is the product of metabolism. ... Efficacy is the ability to produce a desired amount of a desired effect. ... An adverse drug reaction (abbreviated ADR) is a term to describe the unwanted, negative consequences sometimes associated with the use of medications. ... Cardiac arrhythmia is a group of conditions in which the electrical activity of the heart is irregular or is faster or slower than normal. ... Cetirizine hydrochloride (IPA sɛ.ˈtɪɹ.ɪ.ˌzin) is a major metabolite of hydroxyzine, and a racemic selective H1 receptor antagonist used in the treatment of allergies, hay fever, angioedema, and urticaria. ... Loratadine is a drug used to treat allergies. ...

Systemic

• Levocetirizine
• Desloratadine
• Fexofenadine

Levocetirizine (as levocetirizine dihydrochloride) is a third generation non-sedative antihistamine, developed from the second generation antihistamine cetirizine. ... Desloratadine is a drug used to treat allergies. ... Fexofenadine hydrochloride (brand names include Allegra® and Telfast®) is an antihistamine drug used in the treatment of hayfever and similar allergy symptoms. ...

Other agents

Inhibitors of histamine release

These agents appear to stabilise the mast cells to prevent degranulation and mediator release.

• Cromoglicate (cromolyn)
• Nedocromil

Cromoglicate (INN) (also referred to as cromolyn (USAN) or cromoglycate (former BAN)) is traditionally described as a mast cell stabilizer, and is commonly marketed as the sodium salt sodium cromoglicate. ... The introduction to this article provides insufficient context for those unfamiliar with the subject matter. ...

H₂-receptor antagonists

Main article: H₂-receptor antagonist

Clinically-relevant histamine H₂-receptors are found principally in the parietal cells of the gastric mucosa. H₂-receptor "antagonists" are also inverse agonists, rather than true antagonists; and are used to reduce the secretion of gastric acid. Examples include cimetidine, ranitidine, and famotidine. An H2-receptor antagonist, often shortened to H2 antagonist, is a drug used to block the action of histamine on parietal cells in the stomach, decreasing acid production by these cells. ... Parietal cells (also called oxyntic cells) are cells located in the stomach epithelium. ... In anatomy, the stomach is a bean-shaped hollow muscular organ of the gastrointestinal tract involved in the second phase of digestion, following mastication. ... In pharmacology, an inverse agonist is an agent which binds to the same receptor binding-site as an agonist for that receptor but exerts the opposite pharmacological effect. ... Antagonists In medicine and biology, a receptor antagonist is a ligand that inhibits the function of an agonist and inverse agonist for a specific receptor. ... Gastric acid is, together with several enzymes and the intrinsic factor, one of the main secretions of the stomach. ... Cimetidine is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. ... Ranitidine (INN) (IPA: ) is a histamine H2-receptor antagonist that inhibits stomach acid production, and commonly used in the treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD). ... Famotidine is a histamine H2-receptor antagonist that inhibits stomach acid production, and is commonly used in the treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD). ...

H₃- and H₄-receptor antagonists

These are experimental agents and do not yet have a defined clinical use.

H₃-receptor antagonists

• ABT-239
• Thioperamide
• Clobenpropit
• Impromidine
  • • Similar in structure to burimamide
    • Imidazole ring
    • Polar moiety on the side chain - thiourea, isothiourea and guanidine
    • other substituents are highly variable

Burimamide is an H2-receptor antagonist that is largely inactive at physiological pH. Clayden, J. Greeves, N. Warren, S. Wothers, P. (2001). ... Imidazole is a heterocyclic aromatic organic compound. ... The term Side chain can have different meanings depending on the context: In chemistry and biochemistry a side chain is a part of a molecule attached to a core structure. ... Thiourea is related to urea, where an oxygen atom is replaced by a sulfur atom. ... Guanidine is a crystalline compound of strong alkalinity formed by the oxidation of guanine. ...

H₄-receptor antagonists

• Thioperamide

Other agents with antihistaminergic activity

Many drugs, used for other indications, possess unwanted antihistaminergic activity. These include tricyclic antidepressants, antipsychotics, etc. Chemical structure of the tricyclic antidepressant amitriptyline Tricyclic antidepressants are a class of antidepressant drugs first used in the 1950s. ... The term antipsychotic is applied to a group of drugs used to treat psychosis. ...

See also

• H2-receptor antagonist

An H2-receptor antagonist, often shortened to H2-antagonist, is a drug used to block the action of histamine on parietal cells in the stomach, decreasing acid production by these cells. ...

References

• Forneau E, Bovet D (1933). Recherches sur l'action sympathicolytique d'un nouveau derive du dioxane. Arch Int Pharmacodyn 46, 178-91.
• Leurs R, Church MK, Taglialatela M (2002). "H₁-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects". Clin Exp Allergy 32 (4): 489-98. PMID 11972592. 
• Nelson, WL (2002). In Williams DA, Lemke TL (Eds.). Foye's Principles of Medicinal Chemistry (5 ed.). Philadelphia: Lippincott Williams & Wilkins. ISBN 0-683-30737-1
• Rossi S (Ed.) (2004). Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2
• Simons FE (2004, Nov 18). "Advances in H₁-antihistamines". N Engl J Med 351 (21): 2203-17. PMID 15548781 Abstract.