H1 antagonists, also calledH1 blockers, are a class ofmedications that block the action ofhistamine at theH1 receptor, helping to relieveallergic reactions. Agents where the main therapeutic effect is mediated by negative modulation of histamine receptors are termedantihistamines; other agents may have antihistaminergic action but are not true antihistamines.[citation needed]
In common use, the term "antihistamine" refers only to H1-antihistamines. Virtually all H1-antihistamines function asinverse agonists at the histamine H1-receptor, as opposed to neutralantagonists, as was previously believed.[1][2][3]
H1-antihistamines are used clinically to treat histamine-mediated allergic conditions. These indications may include:[4]
First-generation H1-antihistamines can act on the central nervous system. As a result, they are also used for:[5]
H1-antihistamines can be administered topically (through theskin,nose, oreyes) or systemically, based on the nature of the allergic condition.
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, non-sedating antihistamines. First-generation antihistamines includediphenhydramine (Benadryl),carbinoxamine (Clistin),clemastine (Tavist),chlorpheniramine (Chlor-Trimeton), andbrompheniramine (Dimetane). However, a 1955 study of "antihistaminic drugs for colds," carried out by the U.S. Army Medical Corps, reported that "there was no significant difference in the proportion of cures reported by patients receiving oral antihistaminic drugs and those receiving oral placebos. Furthermore, essentially the same proportion of patients reported no benefit from either type of treatment."[6]
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 and their ability to cross theblood–brain barrier.
The most common adverse effect is sedation; this "side-effect" is utilized in manyOTC sleeping-aid preparations. Other common adverse effects in first-generation H1-antihistamines include dizziness,tinnitus, blurred vision,euphoria, incoordination,anxiety, increased appetite leading toweight gain,insomnia, tremor,nausea and vomiting,constipation,diarrhea, dry mouth, and dry cough. Infrequent adverse effects include urinary retention,palpitations,hypotension,headache,hallucination,psychosis anderectile dysfunction.[4][7][8]
The newer, second-generation H1-antihistamines are far more selective for peripheral histamine H1-receptors and have a better 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.[4]
Continuous and/or cumulative use ofanticholinergic medications, including first-generation antihistamines, is associated with a higher risk for cognitive decline and dementia in older people.[9][10]
In type I hypersensitivity allergic reactions, anallergen (a type ofantigen) interacts with and cross-links surface IgEantibodies onmast cells andbasophils. Once the allergen cross-linksImmunoglobulin E, tyrosine kinases rapidly signal into the cell, leading to celldegranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, the histamine can react with local or widespread tissues throughhistamine receptors.[citation needed]
Histamine, acting on H1-receptors, producespruritus,vasodilation,hypotension,flushing,headache,bradycardia,bronchoconstriction, increase invascular permeability and potentiation of pain.[2]
While H1-antihistamines help against these effects, they work only if taken before contact with the allergen. In severe allergies, such asanaphylaxis orangioedema, these effects may be of life-threatening severity. Additional administration ofepinephrine, often in the form of anautoinjector, is required by people with such hypersensitivities.[11]
| Antihistamine | Brand name | Dosea | Time to peak | Half-lifeb | Metabolism | Selective? | Anticholinergic? |
|---|---|---|---|---|---|---|---|
| Cyproheptadine | Periactin | 4–8 mg | 1–3 hours | 8–9 hours | Unknown | No | Yes |
| Diphenhydramine | Benadryl | 50 mg | 2–3 hours | 2–9 hours | CYP2D6, others | No | Yes |
| Doxepin (low-dose) | Silenor | 3–6 mg | 2–3 hours | 17 hoursc | CYP2D6, others | Yes (at low doses) | No (at low doses) |
| Doxylamine | Unisom | 25 mg | 2–3 hours | 10–12 hours | CYP2D6, others | No | Yes |
| Hydroxyzine | Atarax, Vistaril | 25–100 mg | 2 hours | 20 hours | ADH, CYP3A4, others | Yes (at low doses) | No |
| Mirtazapine | Remeron | 7.5–15 mg | 2 hours | 20–40 hours | CYP2D6, others | No | No |
| Quetiapinee | Seroquel | 25–200 mg | 1.5 hours | 7 hoursd | CYP3A4 | No | No (at low doses) |
| Footnotes:a = For sleep/sedation.b = In adults.c Active metabolite nordoxepin half-life is 31 hours.d Active metabolite norquetiapine half-life is 9–12 hours.e Not recommended per literature reviews.Sources: See individual articles for references. See also selected reviews.[12][13][14] | |||||||
Other non-selective sedating antihistamines used as hypnotics include the antihistamineschlorpheniramine andpromethazine, theantidepressantsamitriptyline,trimipramine, andtrazodone, and theantipsychoticsolanzapine,risperidone, andchlorpromazine, among others.[12][15]
These are the oldest H1-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 muscarinicacetylcholine receptor (anticholinergic) antagonists as well. These agents also commonly have action atα-adrenergic receptors and/or5-HT receptors. This lack of receptor selectivity is the basis of the poor tolerability profile of some of these agents, especially when compared with the second-generation H1-antihistamines. Patient response and occurrence of adverse drug reactions vary greatly between classes and between agents within classes.
The first H1-antihistamine discovered waspiperoxan, byErnest Fourneau andDaniel Bovet (1933) in their efforts to develop aguinea pig animal model foranaphylaxis at thePasteur Institute inParis.[16] Bovet went on to win the 1957Nobel 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.
| Class | Description | Examples |
|---|---|---|
| Ethylenediamines | Ethylenediamines were the first group of clinically effective H1-antihistamines developed. |
|
| Ethanolamines | Diphenhydramine was the prototypical agent in this group. Significantanticholinergic adverse effects, as well as sedation, are observed in this group, but the incidence of gastrointestinal adverse effects is relatively low.[4][17] | |
| Alkylamines | Theisomerism is a significant factor in the activity of the agents in this group.E-triprolidine, for example, is 1000-fold more potent thanZ-triprolidine. This difference relates to the positioning and fit of the molecules in the histamine H1-receptor binding site.[17] Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse effects, but relatively greater incidence of paradoxicalcentral nervous system (CNS) stimulation.[4] | |
| Piperazines | These compounds are structurally related to the ethylenediamines and the ethanolamines, and produce significantanticholinergic adverse effects with the exception of hydroxyzine, which has low to no affinity formuscarinic acetylcholine receptors and therefore produces negligible anticholinergic side-effects.[18] Compounds from this group are often used for motion sickness, vertigo, nausea, and vomiting. The second-generation H1-antihistaminecetirizine also belongs to this chemical group.[17] | |
| Tricyclics andTetracyclics | These compounds differ from thephenothiazineantipsychotics in the ring-substitution and chain characteristics.[17] They are also structurally related to thetricyclic antidepressants (andtetracyclics), explaining the H1-antihistaminergic adverse effects of those three 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. |
|
X = N, R1 = R2 = small alkyl groups
X = C
X = CO
Second-generation H1-antihistamines are newer drugs that are much more selective for peripheral H1 receptors as opposed to thecentral nervous system H1 receptors andcholinergic receptors. This selectivity significantly reduces the occurrence of adverse drug reactions, such as sedation, while still providing effective relief of allergic conditions.Most of these compounds have peripheral selectivity because they arezwitterionic at physiological pH (around pH 7.4). As such, they are very polar, meaning they are less likely to cross theblood–brain barrier and act mainly outside the central nervous system.
Examples of systemic second-generation antihistamines include:
Examples of topical second-generation antihistamines include:
H1 receptor antagonists that are approved forover-the-counter sale in the United States include the following.[31]
Common/marketed:
Uncommon/discontinued:
