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The Pink Pill that Puts People to Sleep

Don’t panic, it’s just diphenhydramine.

Dry eyes? Irritated eyes? Try benzalkonium chloride. If it’s really bad, try and get emadastine.

Ever have a hard time breathing because the nose is so congested it feels like there’s a weight on the face? Azelastine might help. If shoving something up into the nose isn’t appealing, loratadine might work just as well.

Looks cool right? Drawings. That last one is oxytocin by the way.

The pictures above all show dermatographic urticaria (also known as skin writing) in action. If someone can do that to himself or herself, it’s best to get some hydroxyzine.

What do all these things have in common? They’re all antihistamines.

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Diphenhydramine is found in Benadryl. Azelastine is the prescribed eye drop called Optivar. Loratadine is found in one of the most common allergy medications today, Claritin. Hydroxyzine is in Atarax, a prescribed pill that works to prevent “skin writing.”

The first antihistamine was introduced in 1942 when Bernard N. Halpern started the first set of clinical trials on humans. The antihistamine used was Phenbenzamine. It wasn’t until 1955 that the anti-allergenic effects of H1-antihistamines were reported. A second set of relatively non-sedating antihistamines were introduced in 1981 and in 1986 the cardiac toxicity of antihistamines is noted. From there, human H-receptors were cloned. H2 in 1991, H1 in 1993, H3 in 1999, and H4 in 2000. By cloning the receptors, scientists are able to develop antihistamines that can interfere better with histamine at the H-receptors. There are over 45 different types of H1-antihistamines in use today and even more in development [4].

H1-antihistamines decrease the allergic inflammation by directly interfering with histamine at the H1-receptors on sensory neurons and small blood vessels. The antihistamine inhibits cell activation and histamine release. The mechanism involved in this has not been fully documented, but the decrease in regulation of intracellular calcium ion build up in largely involved.

H1-antihistamines are divided into 2 classes. The first generation has the ability to readily cross the blood-brain barrier. These tend to occupy H1-receptors on the postsynaptic membrane of histaminergic neurons in the central nervous system. The second generation of H1-antihistamines does not have the ability to cross the blood-brain barrier as easily. Positron emission tomography (PET) is used to record H1-antihistamine in the brain.

The three diagrams below show the molecular basis of action of histamine and antihistamines.

The left side of the diagram shows the inactive state of the histamine H1-antihistamines and the right side the active state. The two states are in equilibrium of one another.

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This diagram shows the agonist, histamine binding to the receptor. Histamine stabilizes the receptor and keeps it in this conformation. Due to its affinity for the active state, the equilibrium shifts towards the active state. The histamine binding to the receptor causes the G to leave the complex and bind to GTP.

H1-antihistamines prefer the inactive state, so in its presence, the equilibrium is shifted towards the inactive state.

H1-antihistamines have its benefits and risks. Since they are able to directly interfere with histamine action they are able to down regulate allergic inflammation indirectly through nuclear factor-κB and calcium ion channels. This allows for quicker effects. While it is quicker, because the H1-antihistamines cross the blood-brain barrier and occupy central nervous system H1-receptors, this causes impairment of central nervous system function. So the more H1-receptors that are occupied, the higher the impairment of CNS functions.

In the first generation of H1-antihistamines, there is a higher chance of adverse effects in the body than the second generation. The first generation has a poor selectivity for H1-receptors. The antimuscarinic side effects range from mydriasis, dry eyes/mouth, constipation, and urinary hesitancy and retention [4]. The antiserotonin side effects include and increase in appetite and increase in weight. First generation H1-antihistamines can also impair the immune response to bacterial infections. This is due to coadministration of H2-antihistamines. These adverse effects are due to H1-antihistamines binding to H1-receptors. PET studies have shown that at standard

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doses, H1-antihistamines occupy more than 70% of CNS H1-receptors. The high level of occupation is due to their ability to penetrate the blood-brain barrier. This is due to their lipophilicity, low molecular weight, and lack of recognition by the P-glycoprotein efflux pump [3]. An overdose in H1-antihistamines can potentially lead to extreme drowsiness, confusion, delirium, coma respiratory depression, and if not treated, death. Since H1-antihistamines interfer with calcium channels, this also messes with potassium and sodium channels. These ion channels are key cardiac ion currents and by interfering with them, cardiac toxicity is common with overdosing of H1-antihistamines.

While first generation H1-antihistamines are full of adverse CNS effects, second generation H1-antihistamines are different. They are relatively free from many of the adverse effects the first generation has. Compared to the first generation, second generation H1-antihistamines do not have as easily as a time penetrating the blood-brain barrier. They occupy less than 20% of the central nervous system H1-receptors [3]. Second generation H1-antihistamines have less sedating effects than the first generation (ie: Claritin VS Benadryl).

H2-antihistamines exist but are not true antagonists like H1-antihistamines. They are found mostly in parietal cells of the gastric muscosa. H3-antihistamines and H4-antihistamines are still considered experimental agents and are not yet cleared for clinical use. Three and four are in human trials and studies are investigating the use of H3-antihistamines to treat conditions such as ADHD, Alzheimer’s and schizophrenia [4].

H1-antihistamines weren’t always called H1-antihistamines. They were originally termed H1-receptor antagonist. They were renamed because histamine actually acts as an agonist by stabilizing the activated conformation of the H1-receptor. The H1-antihistamines actually act as inverse agonists or neutral antagonists. Due to this, all H1-antihistamines examined to date are inverse agonists [2].

Antihistamines have been is use since 1942 and even today are still being studied and tested. Currently H1-antihistamines make up the most of antihistamines with two separate generations. H3-4-antihistamines are still being tested and have no uses as of now. Antihistamines can be found in many different medications that treat symptoms related to allergies.

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Works Cited

1. "Antihistamines for Allergies: Types and Side Effects." WebMD. WebMD, n.d. Web. 22 Feb. 2014.

2. Leurs R., Church MK., Taglialatela M. “H-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects.” Clin. Exp. Allergy. (2002) 32: 489-98

3. McAuley, David. "Low,  Non-sedating, and Common Antihistamines." Low, Non-sedating, and Common Antihistamines. N.p., 21 Feb. 2013. Web. 23 Feb. 2014.

4. Simons and K. J. Simons, “Histamine and H1-antihistamines: celebrating a century of progress,” Journal of Allergy and Clinical Immunology, vol. 128, no. 6, pp. 1130–1150, 2011.

5. Yu, F. Bonaventure, P. Thurmond, RL. “The fugure antihistamines: histamine H3 and H4 receptor ligands.” Adv Exp Med Biol. 2010. 709:125-40.