Chemistry of Antihistamines, Nothing to Sneeze At

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Springtime in Chapel Hill

March in North Carolina brings out one of the country’s greatest rivalries. No, I’m not talking about UNC vs Duke basketball. I’m talking about when the flowers start to bloom in the Tar Heel state, and pandemonium ensues. North Carolinians run to their local pharmacy to pick up their preferred allergy medication: according to US News and World Report, cetirizine (Zyrtec) and loratadine (Claritin) are neck-in-neck for the top pharmacist-recommended over-the-counter allergy medication. As an organic chemist and sufferer of seasonal allergies myself, I was curious: how do antihistamines work, and is one better than the other?

To understand the differences between these two medications, we need to go back to 1910, when histamine (aptly named for containing an amine, or NH2, in the structure) was first studied. Histamine is a small molecule that is formed from the amino acid histadine through enzymatic removal of carbon dioxide. Histamine is released when allergens enter the body. It can then bind to a four G protein-coupled receptor which causes the allergy symptoms we are familiar with, including itchy eyes, stuffy nose, and sneezing.

Histamine vs Diphenhydramine

Antihistamine medicines are antagonists that compete with histamine for receptor binding. The first generation of antihistamine drugs, most notably diphenhydramine, (aka Benadryl), sought to mimic histamine.  Histamine and diphenhydramine are small molecules with many structural similarities; scientists determined that the functional groups necessary for histamine binding are an amine, or nitrogen (red), a linker containing 2-3 atoms (green), and an aromatic ring (blue). Antihistamines are more lipophilic than histamine because they have two aromatic groups (blue) and have carbons attached to the nitrogen (instead of hydrogens). Though molecules like diphenhydramine work very well at competitively binding histamine and reducing allergy symptoms, first generation antihistamines are small and structurally simple. Because of this, they have potential to bind to many other receptors in the body and can easily cross the blood brain barrier, creating many side effects including drowsiness.

Second Generation Antihistamines

The second generation antihistamines sought to have higher H1 receptor selectivity and lower brain penetrability. You will notice the second generation antihistamines like cetirizine (Zyrtec) and loratadine (Claritin) have the same important binding features as diphenhydramine, including a nitrogen connected to an aromatic ring via a small linker. This is structurally similar to the linear amine found in Benadryl and binds similarly. However, the major structure change between the first and second generation antihistamines is the addition of a carboxyl (or CO2) group (pink). Though loratadine does not have a carboxyl group as drawn, it is a prodrug: it undergoes a change in the body to make it into the active pharmaceutical molecule. The prodrug reacts with water in the body to form a carboxyl group. Under physiological pH, amines are protonated to form a positive charge, and the -OH of the carboxyl is deprotonated to form a negative charge. When a positive and a negative charge exist in a single molecule, it is called a zwitterion. Because zwitterions do not readily cross the blood brain barrier, many of the adverse side effects (like drowsiness) from the first generation antihistamines are not present in diphenhydramine and cetirizine.

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Zyrtec is an over-the-counter antihistamine.

In general, it is accepted that Claritin and Zyrtec work similarly to one another. Because they bind the same receptor and have similar functional groups, they are seen as equally as effective. Some people react differently to the different active ingredients. Zyrtec starts working faster, sometimes within one hour, but Claritin tends to last longest in the body, which results in longer-lasting side-effects. Additionally, they interact differently with other medications. Loratadine may not be broken down as easily in the presence of erythromycin, cimetidine, and ketoconazole, which can result in increased side effects,but typically does not present a problem. Similarly, theophylline has a similar effect on cetirizine, and can increase drowsiness. Doctors recommend trying both and sticking with the one that seems most effective for you. This spring, I hope that a new understanding of antihistamines helps suppress your symptoms, no matter which allergy medicine you “ah-choose.”

Peer edited by Clare Gyorke.

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