Many of us are familiar with allergies. To put it generally, allergies are the symptoms
of an immune response that occurs when your body encounters something foreign to itself
that it mistakes for something dangerous. This could include things like foods, drugs,
insect bites, pet dander, and pollen. Allergies are exceedingly common,
and as the 6th leading cause of chronic illness in the US, they affect over 50 million Americans,
costing over 18 billion dollars annually. To understand how antihistamines alleviate allergies,
we must understand more about histamine, which is this nitrogenous compound here.
Within the immune system, histamine is released by mast cells in our tissues,
and basophils in our blood, which are cells we described in detail in the immunology series.
This process initiates an inflammatory cascade and a series of effects mediated primarily through
the H1 histamine receptor. It is worth noting at this point; H2, H3 and H4 receptor isotypes
have also been documented, with H2’s physiological function much better understood than the other
two. Although H2 mediates some immunological functions, H2’s primary physiological function
is to aid gastrointestinal motility and promote gastric secretion. To remain in
the context of allergies, we will focus on H1-related antihistamines in this tutorial.
Through the H1 receptor, histamine dilates blood vessels and constricts the cells lining these
vessel walls, causing increased blood flow to an affected area and allowing immune cells from the
blood to escape the vessels and enter inflamed tissues. This can lead to the swelling and
sensation of warmth in tissues, the presence of hives in the skin, and can also cause fluid to be
expelled in the sinuses, leading to a runny nose, teary eyes, and sneezing. Histamine can also act
locally on nerve terminals, causing an itching or painful sensation. Airways constrict in response
to histamine, and the contractile force of the heart can be increased as well. Most importantly,
histamine release initiates an immune response where other immune cells are recruited, additional
pro-inflammatory molecules are released, and inflammation is exacerbated. Antihistamines help
prevent this cascade from occurring, so let’s discuss the mechanism by which this occurs.
Antihistamines do not prevent the release of histamine, but rather inhibit its pro-inflammatory
effects by acting as inverse agonists of the H1 receptor. This works as follows. The H1 receptor
has a high level of basal activity, which means it can undergo spontaneous conformational changes
towards active receptor conformations even in the absence of histamine. Antihistamines can not only
block the effects of histamine through receptor antagonism, preventing histamine from binding,
but also through inverse agonism, suppressing or decreasing the basal activity of the receptor by
stabilizing the receptor’s inactive conformation, thereby reducing the degree of spontaneous
activation. Antihistamines are thus efficacious in relieving allergy related symptoms, but because
inflammation begins with histamine release, and is followed by additional inflammatory signals,
treatment is most efficacious when used prophylactically, meaning in a preventive manner.
In cases of significant histamine release leading to anaphylaxis, which is a severe and potentially
life-threatening allergic reaction, antihistamine treatment is not sufficient. In such a case,
exogenous adrenaline must be used to rapidly counteract the airway constriction and hypotension
induced by histamine. Adrenaline and the receptors adrenaline interact with are of great importance
and will be covered in a future tutorial. In addition to preventing allergies, H1
antihistamines can be used to prevent generalized itching, by acting on peripheral nerve endings;
insomnia, through sedative effects in the nervous system; and motion sickness,
due to inhibition of the “emetic”, or nausea/vomiting response within the brainstem.
Now let’s get more specific about the drugs. There are two generations of H1 antihistamines.
First-generation antihistamines, such as diphenhydramine, commonly known by the
brand name Benadryl, are relatively small and lipophilic molecules, allowing them to cross a
protective barrier that shields our brain, called the blood brain barrier, which we learned about
in the biopsychology series. Once in the brain, the main psychoactive effect observed through
histamine receptor antagonism is drowsiness and sedation. This psychoactive relationship was first
documented in the 1950s and led to an explosion of research interest in psychiatric pharmacology.
Prior to this serendipitous finding, along with a few others, there was a strange reluctance to
accept how profoundly small molecules impact aspects of brain function such as emotion,
behavior, and consciousness. This will be discussed in more detail
when we cover psychiatric pharmacology. In an effort to find compounds that retain
antihistaminergic activity without the psychoactive side effects,
second-generation antihistamines were developed. This includes loratidine,
better known as Claritin; cetirizine, known as Zyrtec; and fexofenadine, known as Allegra. These
compounds cross the blood brain barrier much less readily because they are more lipophobic,
but are also substrates for p-glycoprotein, or PGP, a protein pump within the blood brain barrier
that can efficiently efflux second generation antihistamines that enter the brain space back
into the periphery, preventing these drugs from reaching high levels in the brain and
thereby minimizing their psychoactivity. Second generation drugs are also more specific than
first generation, which have off-target effects on the cholinergic and serotonergic systems.
Both classes of antihistamines are efficacious in symptom prevention,
however second-generation drugs are more often chosen because of their decreased side effects,
due to their greater H1 receptor specificity and lack of central nervous system penetration.
As we discussed, the main side effects of H1 antihistamines are sedation and
anticholinergic effects. Off-target effects in the cholinergic system result in dry mouth, dry eyes,
and urinary retention in rare cases. Additionally, inhibition of the HERG ion
channel within the heart by antihistamines can extend the heart’s QT interval,
which increases the time it takes the heart to reset after a contraction, potentially leading
to dangerous arrhythmias. The antihistamine terfenadine, previously sold as Seldane,
was famously removed from the market in 1997 due to its pro-arrythmetic effects.
Despite this, currently available over-the-counter antihistamines are considered extremely safe for
adults and children over two years old when taken as directed. They are readily available in various
pills, ointments, and nasal sprays, and these help many of us face tough seasonal allergies,
or even put up with our loved one’s pets. And that concludes an introduction to antihistamines.