When people get a cold or hay fever, they usually go to the “allergy” or “colds and flu” sections of the pharmacy and choose one of the dozens of products available for those ailments. Most of those products contain an antihistamine, or two, that stops the sneezing, itching, and runny nose that’s been driving them crazy. They are faced with a difficult decision at that moment because their options are numerous, and they don’t know what medicine to choose. Should I buy a decongestant, an antihistamine, or a combination? In this blog, I hope to explain antihistamines in such a way that you’ll know how they work and which one(s) will help the most.
Antihistamines are “the most commonly used medications in the world…” They block the effects of histamine. Histamine is a “natural body constituent” meaning it’s part of our normal body make-up and is present in many different types of cells in the blood and the body tissues. It is stored in mast cells. Mast cells are found in body tissues that interact with the outside environment (skin, oral-nasal and bronchial lining, GI tract). Histamine is released from the mast cells during inflammatory and allergic reactions an individual experiences. Histamine causes its effects by coming in contact with receptors located on the cells of the tissues being invaded. The most important receptors are called H1 and H2 receptors. Thus, there are two types of antihistamines, H1 and H2 histamine blockers.
H2 receptors are most often found in stomach and facilitate (mediate) the production of stomach acid. H2 blockers, then, reduce the amount of stomach acid and help the symptoms of acid indigestion and reflux. They were marketed for the prevention gastric and duodenal ulcers and the prevention of stress ulcers and upper GI bleeding. It’s important to know about H2 blockers, but our focus here is H1 receptor antihistamines.
H1 receptors are present in the smooth muscle of our respiratory passages, blood vessels, and mucous membrane surface cells. The release of histamine onto these receptors causes itching, pain, congestion of the blood vessels, swelling, and leakage of fluid from the mucous membranes. In response to exposure to a virus or allergen, histamine is released onto the receptors and symptoms develop. Watery, itchy eyes, runny, itchy nose, itchy, swollen throat, difficulty breathing, and sneezing begin, so H1 histamine blockers are the focus of this article since they inhibit the production of histamine and block its effects.
H1 antihistamines are found in more cold and allergy preparations than any other single component. H1 antihistamines can be separated into six different classes based on their chemical composition and method of action. H1 antihistamines are further divided into first and second generation drugs based on whether they are sedating or non-sedating. The big knock against histamine blockers has been that they caused drowsiness and impairment of cognitive and psychomotor functions. First generation antihistamines are notorious for that because they cross the blood-brain barrier thus causing sedation. Second generation H1’s “cross the blood-brain barrier to a minimal extent and are relatively non-sedating and non-impairing,” a significantly more desirable situation. These non-sedating antihistamines are, therefore, the “drugs of choice in the treatment of allergic rhinitis, allergic conjunctivitis, and urticaria [hives].”
As mentioned previously, there are six chemical groups of H1 antihistamines. Within these classes there are first and second generation drugs. Knowing the difference in the six classes is important therapeutically because when tolerance (ineffective use) is developed to a drug in one class, switching to a drug in a different chemical class will often be effective. Below is a list of the classes and examples of first and second generation H1 antihistamines in each group.
Alkylamines: 1st Gen—chlorpheniramine (Chlortrimeton), brompheniramine (Dimetapp).
2nd Gen—acrivastine
Piperazines: 1st Gen—hydroxyzine (Vistaril/Atarax), meclizine (Antivert).
2nd Gen—cetirizine (Zyrtec), levocetirizine (Xyzal).
Piperidines: 1st Gen—azatidine (Optimine), cyproheptadine (Periactin)
2nd Gen—astemizole (Hismanal), fexofenadine (Allegra),
loratadine (Claritin), terfenadine (Seldane), desloratidine (Clarinex).
Ethanolamines: 1st Gen—clemastine, diphenhydramine (Benadryl), dimenhydramine
2nd Gen—NA
Ethylenediamines: 1st Gen—antazoline, pyrilamine, tripelennamine (Pyribenzamine)
2nd Gen—NA
Phenothiazines: 1st Gen—promethazine (Phenergan), methdilazine
2nd Gen—NA
A few of the drugs listed above are not FDA approved and are not available in the U.S. Most are, however, and hopefully have names familiar to you. Some are available over-the-counter and can be purchased at your local CVS or Walgreen’s. Some are by prescription, only. A lot of them can be purchased OTC at a lower dose. For example, Chlortrimeton 4mg and 8 mg, can be purchased without a RX, but Chlortrimeton 12mg, in a time release capsule requires a Rx. The interesting thing is, 4 mg is an ineffective dose. A dose of 8 mg is slightly effective, and 12 mg works fairly well. At the 12 mg dose, however, there is a high likelihood side effects will appear. The same is true for diphenhydramine (Benadryl). Most OTC compounds contain 25 mg of diphenhydramine, a minimally effective dose. Fifty mg, or more, is needed to be effective for the itching from hives, poison Ivy, or hay fever. Benadryl is incredibly sedating so at the effective dose, patients will have drowsiness and dry mouth. I took Benadryl for a cold when I was on my pediatrics rotation in med school. It made me so drowsy I could barely stand let alone stay awake.
Previously, I mentioned how patients develop a tolerance to antihistamines. When that happens, the first thing to do is change to a different class of antihistamine. I developed a familiarity with 2 or 3 drugs in each class and would switch classes when the drug the patient was taking was no longer effective. That seemed to work well.
Second generation, non-sedating antihistamines were clearly more effective and better tolerated than first generation drugs. They were invented for that reason since first generation antihistamines were so sedating. I had particularly good success with hydroxyzine (Atarax/Vistaril) when I prescribed it for itching. It was effective without causing too much drowsiness. For head colds, these drugs are not very effective. I recommended them, though, because patients needed to take something to feel they were treating their cold. If I told them there was nothing they could take that helped, I immediately lost credibility. Taking a medicine is a pro-active move that makes the patient feel better. It is probably an example of the placebo effect, a powerful tool physicians often use.
Since we have available a large number of non-sedating antihistamines, there isn’t a strong reason to use first generation antihistamines any longer. They have unpleasant side effects and require high doses to be effective. Plus intranasal corticosteroids are probably even more effective and may actually be preferable to second generation antihistamines. So what I’m really saying is allergic disorders are successfully treated only by persistently following a trial and error treatment method. It takes cooperation and compliance from the patient and concern and diligence from the physician.
References: Luss LV. Use of antihistamines in a physician’s clinical practice. Ter Arkh 2014;86(8):106-109.
Meltzer EO. Comparative safety of H1 antihistamines. Ann Allergy 1991Dec;67(6):625-633.
Meltzer EO. Performance effects of antihistamines. J Allergy Clin Immunol 1990 Oct;84(4Pt2):613-619.
Chaudhari R, Gosavi S, Bomare P, Sonawane S, Ahire T. An overview of antihistamines and their properties used for treatment of different diseases. Antiinflamm Antiallergy Agents Med Chem 2023;22(4):220-229.
Kawauchi H, Yanai K, Wang D, Itahashi K, Okubo K. Antihistamines for allergic rhinitis treatment from the viewpoint of non-sedative properties. Int J Mol Sci 2019 Jan 8;20(1):213.
Li L, Liu R, Peng C, Chen X, Li J. Pharmacogenomics for the efficacy and side effects of antihistamines. Exp Dermatol 2022 July;31(7):993-1004.
Simons FER, Simons KJ. H1 Antihistamines: Current Status and Future Directions. World Allergy Org 2008 Sep:145-xx.
