Antihistamines are among the most valued over-the-counter (OTC) medications to the United States healthcare system. These non-prescription medications address health conditions characterized by respiratory issues, skin issues, and many more (9).
These OTC medications work by targeting histamine receptors throughout the body. By binding to these sites, antihistamines can effectively reduce the influence of histamine molecules which are known to produce symptoms of allergic response such as indigestion, dry or itchy eyes, runny nose, and itchy skin.
Table of Contents
Introduction
Histamine plays a pivotal role in the response to allergens in the human body. Histamine receptors are located throughout the human body and have been classified into categories H1, H2, H3, and H4.
Generally speaking, H1 receptors account for neuronal and nervous system sites, H2 are more related to stomach and digestive function, H3 receptors are found in the brain, and H4 are found in organs and bone marrow. Both H1 and H2 receptors are found in airway tissues, skin tissue, and immune cells.
There is ample research describing the role H1 and H2 receptors play in a myriad of human biology. However, the role of H3 and H4 receptors is not well-understood. I suggest reading this article for a detailed explanation on the role different types of histamine receptors play in the human body.
Antihistamines
Antihistamines are compounds, available by prescription, OTC, and as natural supplements, that interact with the body’s histamine receptors causes a range of different responses. These applications may include the reduction of dry itchy eyes, itching skin or rashes, and even respiratory issues. In some cases, antihistamines may cause drowsiness by acting on histamine receptors located in the central nervous system.
Given the range of different histamine receptors in the body, it is easy to guess there are a range of different antihistamines available to selectively target them. H1 and H2 antihistamines are generally the focal point of any antihistamine discussion. Knowing a bit about each can prove useful when weighting potential benefits of histamine-based therapies.
H1 Antihistamines
H1 antihistamines are readily available in one of two primary forms: first and second generation. These compounds behave similarly, but second generation antihistamines do not cause sedation. Antihistamine products labeled as Non-Drowsy fall into this category. Save cases where sedation may be viewed as favorable, research suggests second generation H1 blockers offer superior results.
First Generation H1 Antihistamines
While still effective at blocking H1 receptor activation, first-generation antihistamines bind to histamine receptors in the brain causing drowsiness. Diphenhydramine, commonly sold under the trade name Benadryl, is an example of one popular H1 antihistamine. Below is a list of first generation H1 blockers and their common Trade Names.
| Active Ingredient | Common Names |
|---|---|
| Diphenhydramine | Benadryl |
| Hydroxyzine hydrochloride | Atarax |
| Chlorpheniramine | Chlortrimeton |
| Doxepin hydrochloride | Doxepin |
| Clemastine | Tavist |
A Word of Warning
The Global Allergy and Asthma European Network (G2LEN) has taken the position that, given a review of all reports of deleterious side effects and related accidents, first-generation H1 blockers should be limited to prescription-used only (7).
Second generation H1 antihistamines
Second generation antihistamines provide similar action as first generation with less sedating effects. These types of antihistamines have their action limited mostly to peripheral tissues and do not directly impact the nervous system (3).
Some studies indicate that second-generation H1 blockers may provide an immunomodulatory action not found among first-generation antihistamines (or at least not well-documented) (5). Below is a list of second generation H1 blockers and their common Trade names:
| Active Ingredient | Common Names |
|---|---|
| Fexofenadine | Allegra |
| Loratidine | Claritin |
| Desloratidine | Clarinex |
| Levocetirizine | Xyzal |
| Cetirizine | Zyrtec |
| Ketotifen | Zaditor |
H1 Antihistamine Absorption & Metabolism
Drug dosing guidelines are established partly based on metabolic study describing the rate (onset) and completeness they enter the bloodstream (bioavailability).
In addition, considerations such as metabolites and possible interactions on drug-clearing metabolic pathways must be considered. Below is a table illustrating expected onset and duration of action for several popular H1 antihistamines.
| H1 Drug | Onset (hrs.) | Duration (hrs.) |
|---|---|---|
| Acrivastine | 0.5 | 8 |
| Cetirizine | 0.7 | ≥24 |
| Desloratadine | 3 | ≥24 |
| Ebastine | 1–3 | ≥24 |
| Fexofenadine | 1–2 | 24 |
| Levocetirizine | 0.5 | >24 |
| Loratadine | 3–4 | 24 |
| Mizolastine | 1 | 24 |
Simons, 2002
Also worth noting is that certain drugs produce potentially toxic byproducts of their metabolism. While not displayed in the table above, Desloratadine is known to produce as many as 6 metabolic byproducts and Loratadine is known to produce as many as 12 (1).
Note: Research suggests that not only is fexofenadine (Allegra) more effective than other popular H1 blockers like Diphenhydramine (1), but also that it avoids toxicity of the central nervous system at doses multiple times higher than manufacturer recommendations (2).
H2 Antihistamines
H2 histamine receptors are located throughout the body similarly to H1 receptors but are also found in high concentration in the digestive system. Histamine is one of the primary signaling molecules for gastric acid secretion and heavily involved in digestive processes (8).
H2 blockers are commonly prescribed for conditions where limiting the amount of stomach acid is deemed favorable, such as GERD. H2 antihistamines still work as histamine receptor antagonists like H1 blockers–they just elicit reactions from predominately different locations in the body. Below is a list of common H2 blockers:
| H2 Drug | Common Name |
|---|---|
| Nizatidine | Axid |
| Famotidine | Pepcid |
| Cimetidine | Tagament |
| Ranitidine | Zantac |
H3 & H4 Antihistamines
The role of H3 and H4 histamine receptors is still unclear, at least compared to current working knowledge regarding H1 and H2 receptors. H3 and H4 targeting antihistamine compounds are available mostly as laboratory supplies and not currently available to consumers as prescriptions or as OTC medications.
Initial research has shown that H3 and H4 receptors may play a pivotal role in cases where common allergic responses are noted (6). Also worth noting is that these receptors have been observed to act independently of mast cells, which are common mediators of histamine release.
Other Allergy Drugs
Antihistamines are often used to address conditions indirectly related to histamine issues such as Mast Cell disorders (MCAD, MCAS, Mastocytosis), food allergies, and autoimmune conditions like rheumatoid arthritis.
In many cases, histamine-related conditions may also utilize compounds targeting prostaglandin, leukotriene inhibitors, and mast-cell stabilizers. These compounds may be used in conjunction with antihistamines, even offering similar beneficial outcomes, but do not target the same receptor sites (10).
References
- Simons, F. E. R. “Comparative Pharmacology of H1 Antihistamines: Clinical Relevance.” The American Journal of Medicine, vol. 113 Suppl 9A, no. 9, 2002, pp. 38S-46
- Hindmarch, I., Z. Shamsi, and S. Kimber. “An evaluation of the effects of high‐dose fexofenadine on the central nervous system: a double‐blind, placebo‐controlled study in healthy volunteers.” Clinical & Experimental Allergy 32.1 (2002): 133-139.
- de Benedictis, F. M., D. de Benedictis, and G. W. Canonica. “New Oral H1 Antihistamines in Children: Facts and Unmeet Needs.” Allergy (Copenhagen), vol. 63, no. 10, 2008, pp. 1395-1404.
- Parsons, Mike E, and C Robin Ganellin. “Histamine and its receptors.” British journal of pharmacology vol. 147 Suppl 1,Suppl 1 (2006): S127-35.
- Assanasen, Paraya, and Robert M. Naclerio. “Antiallergic anti-inflammatory effects of H1-antihistamines in humans.” Clinical allergy and immunology 17 (2002): 101-139.
- Dunford, Paul J., MSc, et al. “Histamine H4 Receptor Antagonists are Superior to Traditional Antihistamines in the Attenuation of Experimental Pruritus.” Journal of Allergy and Clinical Immunology, vol. 119, no. 1, 2007, pp. 176-183. doi: 10.1016/j.jaci.2006.08.034
- Church MK, Maurer M, Simons FER, Bindslev‐Jensen C, van Cauwenberge P, Bousquet J, Holgate ST, Zuberbier T. Risk of first‐generation H1‐antihistamines: a GA2LEN position paper. Allergy 2010; 65: 459–466.
- Bertaccini, G, and G Coruzzi. “Control of gastric acid secretion by histamine H2 receptor antagonists and anticholinergics.” Pharmacological research vol. 21,4 (1989): 339-52
- Consumer Healthcare Products Association (CHPA). “The Value of OTC Medicines to the U.S. Healthcare System,” Research Reports; March 1, 2019.
- Cobanoğlu, Bengü et al. “Role of leukotriene antagonists and antihistamines in the treatment of allergic rhinitis.” Current allergy and asthma reports vol. 13,2 (2013): 203-8.
