Antihistamines are drugs that counteract the effects of histamine in the body, such as allergies and gastrointestinal conditions. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides relief from nasal congestion, sneezing, or hives caused by pollen, dust mites, or animal allergy with few side effects. 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. Consultation of a medical professional is recommended for those who intend to take antihistamines for longer-term use.
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 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.
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). Other antihistamines also target H3 receptors and H4 receptors.
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 antagonists.
Medical uses Histamine makes blood vessels more permeable (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. Antihistamines can also help correct Eustachian Tube dysfunction, thereby helping correct problems such as muffled hearing, fullness in the ear and even tinnitus.
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 to complement standardized treatment of acne due to their anti-inflammatory properties and their ability to suppress sebum production.
Types H1-antihistamines
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 both block the binding of histamine, and reduce its constitutive activity, an effect which is opposite to histamine's. Most antihistamines are inverse agonists at the H1 receptor, but it was previously thought that they were antagonists.
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 that 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, leads 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, 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, with high doses, second-generation antihistamines begin to act on the central nervous system and thus can induce drowsiness when ingested in higher quantities.
List of H1 antagonists/inverse agonists
Acrivastine Alimemazine (a phenothiazine used as antipruritic, antiemetic and sedative) Amitriptyline (tricyclic antidepressant) Amoxapine (tricyclic antidepressant) Aripiprazole (atypical antipsychotic, trade name: Abilify) Brexpiprazole (atypical antipsychotic, trade name: Rexulti) Azelastine Bilastine Bromodiphenhydramine (Bromazine) Brompheniramine Buclizine Carbinoxamine Cetirizine (Zyrtec) Chlophedianol (Clofedanol) Chlorodiphenhydramine Chlorpheniramine Chlorpromazine (low-potency typical antipsychotic, also used as an antiemetic) Chlorprothixene (low-potency typical antipsychotic, trade name: Truxal) Chloropyramine (first generation antihistamine marketed in Eastern Europe) Cinnarizine (also used for motion sickness and vertigo) Clemastine Clomipramine (tricyclic antidepressant) Clozapine (atypical antipsychotic; trade name: Clozaril) Cyclizine Cyproheptadine Desloratadine Dexbrompheniramine Dexchlorpheniramine Dimenhydrinate (used as an antiemetic and for motion sickness) Dimetindene Diphenhydramine (Benadryl) Dosulepin (tricyclic antidepressant) Doxepin (tricyclic antidepressant) Doxylamine (most commonly used as an over-the-counter sedative) Ebastine Embramine Fexofenadine (Allegra/Telfast) Fluoxetine Hydroxyzine (also used as an anxiolytic and for motion sickness; trade names: Atarax, Vistaril) Imipramine (tricyclic antidepressant) Ketotifen Levocabastine (Livostin/Livocab) Levocetirizine (Xyzal) Levomepromazine (low-potency typical antipsychotic) Loratadine (Claritin) Maprotiline (tetracyclic antidepressant) Meclizine (most commonly used as an antiemetic) Mianserin (tetracyclic antidepressant) Mirtazapine (tetracyclic antidepressant, also has antiemetic and appetite-stimulating effects; trade name: Remeron) Olanzapine (atypical antipsychotic; trade name: Zyprexa) Olopatadine (used locally) Orphenadrine (a close relative of diphenhydramine used mainly as a skeletal muscle relaxant and anti-Parkinsons agent) Periciazine (low-potency typical antipsychotic) Phenindamine Pheniramine Phenyltoloxamine Promethazine (Phenergan) Pyrilamine (crosses the blood–brain barrier; produces drowsiness) Quetiapine (atypical antipsychotic; trade name: Seroquel) Rupatadine (Alergoliber) Setastine (Loderix) Setiptiline (or teciptiline, a tetracyclic antidepressant, trade name: Tecipul) Trazodone (SARI antidepressant/anxiolytic/hypnotic with mild H1 blockade action) Tripelennamine Triprolidine
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 the 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 ABT-239 Ciproxifan Conessine A-349,821. Thioperamide
H4-antihistamines
H4-antihistamines inhibit the activity of the H4 receptor. Examples include:
Thioperamide JNJ 7777120 VUF-6002
+Histamine receptors Receptor Location Mechanism of action Function Antagonists Uses of antagonists H1 Throughout the body, especially in: Gqileum contraction modulate circadian cycle itching systemic vasodilatation (indirect effect throughout the increased production of NO) bronchoconstriction (allergy-induced asthma)H1-receptor antagonists Azelastine Diphenhydramine Loratadine Cetirizine Fexofenadine Clemastine Rupatadine H2 Gs ↑ cAMP2+speed up sinus rhythm Stimulation of gastric acid secretion Smooth muscle relaxation Inhibit antibody synthesis, T-cell proliferation and cytokine productionH2-receptor antagonists Ranitidine Cimetidine Famotidine Nizatidine H3 Gi Decrease Acetylcholine, Serotonin and Norepinephrine Neurotransmitter release in CNS Presynaptic autoreceptorsH3-receptor antagonists ABT-239 Ciproxifan Clobenpropit Thioperamide H4Immune system lymphocytes leukocytes Lymphoid organs thymus spleen liver gastrointestinal tract (GIT) pancreas bile ducts Gimediate mast cell chemotaxis. H4-receptor antagonists Thioperamide JNJ 7777120 , no clinical uses exist.Potential uses include: Chemical structure
H1-antihistamines H1-antihistamines are mainly used to treat allergy or other types of inflammatory processes related to IgE production. Most drugs from this class act as histamine inverse agonists rather than neutral antagonists, which means they decrease the constitutive activity of the histamine receptor below its basal level.
This activity is closely related to the general chemical structure of H1-antihistamines:
One aromatic group (such as a phenyl, substituted phenyl, thienyl, or pyridyl), that mimics hitamine's imidazole group; A second aromatic group, which provides extra affinity to the receptor; A spacer, which is usually a short chain of two or three carbons; An end amine group, typically a tertiary aliphatic amine with simple alkyl substituents, that mimics hitamine's end amine group.
From there, you can classify almost any first-generation H1-antihistamine: