Antihistamines - first generation vs second generation

Nov 19, 2019

By Trevor Shewfelt, Pharmacist at the Dauphin Clinic Pharmacy

"Success is stumbling from failure to failure with no loss of enthusiasm." For worse, but mostly for better, that quote from Winston Churchill seems to have ruled my life. I wanted to be an astronaut, but my eyesight was too poor. I wanted to go to the Olympics in Windsurfing, but I had trouble winning a single sailing race. I wanted to be a physicist. As a physics student, I even got an award from the Natural Sciences and Engineering Research Council of Canada (NSERC) to work at the particle accelerator, TRIUMF, in Vancouver for a summer. But I was too dumb to be a physicist. I kinda fell into pharmacy by accident, but have enjoyed the profession ever since.

Another quote is responsible for the article this week. "Did you hear that Benadryl is killing people?" Doris was watching the TV news and yelling at me as I was trying to get out the door. After a few years of marriage, greetings like "Good bye dear. Have a nice day" get so worn and tired.

The Canadian Society of Allergy and Clinical Immunology (CSACI) doesn't like first-generation antihistamines like Benadryl or diphenhydramine, and hydroxyzine or Atarax. The CSACI says first-generation antihistamines "have significant and common side effects including sedation, impairment with decreased cognitive function, poor sleep quality, dry mouth, dizziness, and orthostatic hypotension. These drugs have also been found to result in death from accidents, intentional or unintentional overdoses, and sudden cardiac death."

Let's back up a bit and talk about allergies. If you get a sudden itch, or running nose or watery eyes, it could be an allergy. To treat allergic reactions, one of the types of medication we often reach for are antihistamines. Oral antihistamines have been used for itchy watery eyes and runny noses since the 1940's. Antihistamines block the H1 histamine receptor inside the nose, lungs, eyes and skin.

Allergic reactions start more or less the same way. Your body comes in contact with the substance which you are allergic to, which is called the allergen. Certain cells in your immune system release a chemical messenger called histamine in response to the allergen. The histamine fits into the H1 histamine receptor like a key into a lock which activates the H1 receptor. The activated H1 receptor tells your body to start having allergy symptoms like a runny nose, or an itchy rash. The easiest and best way to avoid an allergic reaction is to identify and avoid the allergen. For example, if you are allergic to the cat at your mother-in-law's house, avoid your mother-in-law. If that horrible cologne your wife bought gives you an itchy rash, don't use it. Simple, right? Well, even if we can identify the allergen, sometimes they are hard to avoid. If you are allergic to pollens that are common in Manitoba, you will probably get a stuffy nose in the spring no matter what you do. So if we can't identify and avoid the allergen, we may need to block the H1 histamine receptor with a medication.

We block the H1 histamine receptor with antihistamines. There are two basic types of antihistamines, first generation and second generation. They both work well, but their differences are speed, staying power and side effects. The first generation antihistamines are have names like chlortripolon (chlorpheniramine), and benadryl (diphenhydramine). First generation antihistamines block the H1 histamine receptor, but they also block other receptors. We call them poorly selective. That leads to some of their side effects like dry mouth, because they affect other receptors. First generation antihistamines are also lipophilic which means they can get through the blood brain barrier. The fact first generation antihistamines can get into the brain and effect histamine receptors there, leads to side effects like drowsiness. In summary, they are work quite well, but they also often cause drowsiness, and some other side effects like dry mouth, urinary retention, and worsening glaucoma. They work fast, which is great if you have a runny nose or an itchy rash, but they don't last that long and you may have to take several pills a day.

Second generation antihistamines cause much less sedation, last longer and have far fewer side effects. Second generation antihistamines are much more likely to only block the H1 receptor. We say this makes them much more selective. So we get fewer side effects like dry mouth. Second generation antihistamines are much less lipophilic. This means they are far less likely to get across the blood brain barrier and cause problems like sedation. These are agents like reactine (cetirizine), claritin (loratadine), aerius (desloratidine) and allegra (fexofenadine). A nice benefit is one pill often lasts all day. Reactine is good for both runny noses and itchy rashes, but I have seen it make some people sleepy. Claritin only works well on runny noses, but it is much less likely to make someone sleepy. So they work well, but have fewer side effects and more staying power.

Should first generation antihistamines like diphenhydramine or Benadryl be banned or put behind the counter? Well, maybe. For most healthy adults on no other medications, it would be difficult, but not impossible to hurt yourself on a first generation antihistamine if you took it according to the package instructions. But it is easier to hurt children with the older antihistamines. It is easier to take too much older antihistamine and get into a car and cause an accident because you were impaired. It is easier for older adults with dementia or enlarged prostate have their conditions get worse because of an antihistamine. Like everything else, we have to weigh the benefit versus the risk. The new antihistamines work very well. The newer antihistamines are so much safer than the older ones. Maybe it is time to put first generation antihistamines behind the counter.

Who was the first ski jumper to win three gold medals at an Olympics games? Matti Nykanen from Finland. In the Olympics before the fall on the Berlin Wall, how many bobsled medals did East Germany win? Three. These were both impressive athletic achievements that took years of training and dedication to fulfill. But they aren't what I remember from the 1988 Calgary Olympics. And there haven't been movies made of either of these accomplishments. I remember of sprinters from Jamaica stumbling into unlikely success in bobsled. They were immortalized in the movie Cool Runnings. I remember a skier from Britain won soared into our hearts on enthusiasm alone. The 2016 bio pic of the same name showed Eddie the Eagle kinda stumble into ski jumping because he wanted to get to the Olympics at something. Enthusiastically stumbling from failure to failure isn't all bad. Maybe Churchill was right and that is the best way to find success. For all the trials and tribulations that happen today, I hope you stumble and soar like an Eagle.

The information in this article is intended as a helpful guide only. It is not intended to be used as a substitute for professional advice. If you have any questions about your medications and what is right for you see your doctor, pharmacist or other health care professional.

As always if you have any questions or concerns about these or other products, ask your pharmacist.

Global and Mail article on Benadryl -

CSACI position statement -


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