Anh.Duong

=Comparison of various H1-antihistamines for allergy treatment=

Abstract
Antihistamines were discovered over seventy years ago and have been recognized as highly effective treatments for allergic diseases. Among different types of antihistamine, H1 receptor inverse agonists (or H1-antihistamines) are the most prescribed drugs on the market due to their high efficacy against allergy. This study gave some general information about the history of use of these medications and how they actually work to treat allergic reactions. Then it went deep into their basic structures to learn how little modifications in the structures may create new generations of H1-antihistamine with higher clinical efficacy as well as reduced side effects. The use of these medications has been associated with sedation, the most frequently occurring undesirable effect in allergy treatment. This study also summarized a variety of clinical research around the country to provide general knowledge of how these H1-antihistamines were tested for their efficacy and side effects. Through literature review, three generations of H1-antihistamines were compared to one another to see what made the next generation better than the previous one so that new directions can be drawn for the development of novel antihistamines in the future. The first generation H1-antihistamines are still very effective against allergy in spite of their side effects while the second and the third generation H1-antihistamines have their structures optimized to increase binding affinity to the H1-receptor lessen the side effects.

Allergy and its causes
A person may easily tell the names of several allergic diseases such as asthma, food or drug allergy, but not everyone can define what allergy really is. According to the report of the Nomenclature Review Committee of the World Allergy Organization (WAO), allergy is defined as "a hypersensitivity reaction initiated by specific immunologic mechanisms".[1] Immunoglobulin E (IgE) antibodies play an important role in most allergic reactions. When an allergen, an antigen capable of stimulating a hypersensitivity reaction, is encountered, it crosslinks IgE bound to Fc receptor found on mast cells or blood basophils, triggering an allergic response that results in the secretion of the pharmacologically active mediator histamine.[2] Histamine (2-[4-imidazolyl]-ethylamine), compound **1**, is a chemical released mainly by basophils and mast cells during degranulation in response to allergic stimuli (Figure 1). It activates histamine receptors, causing inflammation, redness, itching, and swelling.[3]

Definition of an antihistamine and history of use
To lessen the effects of **1**, a histamine inverse agonist (previously defined as an antagonist and now called antihistamine) is used. [4] Antihistamines compete with **1** for binding sites at the receptors.[5] In 1937, the first antihistamine, adrenolytic benzodioxan, was discovered by Daniel Bovet, an Italian pharmacologist, who won the 1957 Nobel Prize in Physiology or Medicine for his work on antihistamines.[4] In 1942, phenbenzamine (Antergant), the first H1-antihistamine for clinical use was discovered.[4] Since then many other antihistamines has been discovered and widely used in the treatment of various allergic diseases.

Different types of antihistamine
Histamine can bind to four different types of histamine receptor: H1, H2, H3, and H4.[4,5,6] Through these receptors, extracellular signals are transported to intracellular second messenger systems with the help of G proteins and trigger downstream events.[4] H1-antihistamines have been used for allergic treatment for years while some research has recently shown H4-antihistamines may become a more effective inverse agonist to treat allergic diseases in the future.[5,6] H2-antihistamines are currently used to treat peptic ulcer and gastroesophageal reflux disease while H3-antihistamines are being investigated for treating obesity and Alzheimer’s disease.[4,7]

The importance of H1-antihistamine
The Gαq11-coupled H1-receptor is responsible for most allergic diseases. It can activate many signaling pathways resulting in the formation of cyclic guanosine monophosphate (cGMP), phospholipase A2, C, D, and an increase in intracellular Ca2+ ions. [4] As a result, H1-antihistamine has been the largest class of medications for allergy treatment with more than 45 drugs available all over the world.[8] This research study only focused on comparing the features, the efficacy, and the side effects of different generations of H1-antihistamines used to treat allergy.

Clinical use of H1-antihistamine
H1-antihistamines are used in the treatment of many allergic diseases: rhinitis, conjunctivitis, dermatitis, urticaria, food allergy, drug allergy, and insect bite allergy. Rhinitis is an IgE-mediated symptom causing stuffy and runny nose, sneezing, nasal itching especially during the spring when there is a high amount of pollen in the air.[1] Conjunctivitis (also called “pink eye”) is an IgE-mediated symptom causing inflamed conjunctiva.[9] It is also called rhinoconjunctivitis because it often accompanies rhinitis.[1] Dermatitis is a general term for the inflammation of the skin, and eczema is an example. Besides that, dermatitis may occur when the skin is in contact with chemicals, fragrances, and urushiol from the poison ivy plants. [1] Urticaria is either an IgE-mediated or an immune complex-associated symptom when there is a contact with the allergen (e.g. latex allergy).[1] Food allergy is an immunologic response resulting from the ingestion of a specific type of food. Drug allergy is an allergic reaction to a medication. Insect bite allergy is an allergic reaction to insect venom (e.g. bee sting).[1]

Basic structural features of H1-antihistamines
Figure 2 shows a typical structure of a H1-antihistamine with several key features: the aryl rings, the terminal amine, the connecting atom X, and multiple of CH2 groups. The aryl rings (commonly phenyl, substituted phenyl, and heteroaryl groups) are important sites for H1-antihistamines to interact with H1-receptors, contributing to the lipophilicity of the whole structure.[4] Lipophilicity can be expressed as log P, indicating the partition of a given compound over an organic solvent and water. The log P value of 2 is correlated with the optimal penetration of the blood-brain barrier.[10] The terminal amine can be a simple alkylamine like dimethylamine or part of a heterocyclic structure such as piperazine, piperidine, phenothiazine. It is protonated when bound on the receptor and very important for stable salt formation.[11] The connecting atom X can be a carbon, oxygen, or nitrogen atom. Chirality at X and having the aryl rings in different planes increase the potency of the drug.[11] Several CH2 groups (maybe 2 or 3 groups) together with the connecting atom forms a spacer group between two aryl rings and the terminal nitrogen atom. Depending on their structures, H1-antihistamines can be divided into six different classes: alkylamine, piperazine, piperidine, ethanolamine, ethylenediamine, and phenothiazine (Table 1).[11] Alkylamine class has a basic structure of an amine with nitrogen atom bonded to three alkyl groups. Piperazine and piperidine are two similar classes with the basic structure having a heterocyclic ring with one or two nitrogen atoms on it. Ethanolamine and ethylenediamine are also two similar classes with the basic structure having two CH2 groups between two nitrogen atoms or one nitrogen atom and one oxygen atom. The structure of phenothiazine class basically has one heterocyclic ring of sulfur and nitrogen in the middle with two benzene rings on its left and right sides.

Several different antihistamines were discovered just by substituting a group on the previous one with a different group so that they may have better efficacy or fewer side effects. For example, diphenhydramine (Benadryl), compound ** 2 **, the most widely used H1-antihistamine,[8] was created by just adding another ring to the structure of ethanolamine (Figure 3).
 * Table 1**. Basic structures of different antihistamine classes (created using ACD/ChemSketch)
 * Class || Alkylamine || Piperazine || Piperidine || Ethanolamine || Ethylenediamine || Phenothiazine ||
 * Structure || [[image:AD_Alkylamine.JPG width="97" height="97"]] || [[image:AD_Piperazine.JPG width="133" height="45"]] || [[image:AD_Piperidine.JPG width="136" height="43"]] || [[image:AD_Ethanolamine.JPG width="173" height="86"]] || [[image:AD_Ethylenediamine.JPG width="151" height="122"]] || [[image:AD_Phenothiazine.JPG width="112" height="72"]] ||

Common features
Most of widely used first generation H1-antihistamines are in the ethanolamine class.[4] Some of them have their structures shown in figure 4 below. Diphenhydramine (**2**), is an old but still one of the most widely used H1-antihistamine on the market for relieving insomnia and allergy.[8] Carbinoxamine (Clistin, Palgic), compound **3**, is an anti-allergic drug only for adults or children ages 3 or older.[12] Doxylamine (Unisom), compound **4**, is the second most powerful antihistamine, also known as a very effective over-the-counter sedative.[13] Clemastine (Tavist), compound **5**, is another sedating antihistamine, but it may have fewer side effects than other first generation H1-antihistamines.[14] Looking at the structures of these antihistamines, we can see that they are very similar to one another. All of them have two aryl rings, either containing a benzhydryl part (two benzene rings adjoining a single carbon) like in **2** and **5** or having one benzene ring and one pyridine ring instead like in **3** and **4**. The chloride added to the benzene ring like in **3** and **5** was shown to increase the antihistaminic activity of the compound.[15]

Efficacy
There have not been many detailed studies on the efficacy of first generation H1-antihistamines due to the lack of clinical trials.[11] According to the research by Simons, the time elapsed (Tmax) for the medication to get into the body and its plasma concentration to reach the maximum value after dosing for most first generation H1-antihistamines is within 3 hours (ranging from 1.7 hours for **2** to 2.8 hours for chlorpheniramine).[11] Duration of action is 12 hours for **2** and 24 hours for chlorpheniramine and hydroxyzine. Usual adult dose of **2**, doxepin, hydroxyzine is 25-50 mg every 6-8 hours daily.[11,16]

Adverse drug reactions
The most undesirable side effect of antihistamines is sedation.[11,16] First generation H1-antihistamines bind to H1-receptors, causing decreased neurotransmission in the central nervous system (CNS) and blockade of muscarinic, α-adrenergic, and serotonin receptors. The effects of the decreased activities of these receptors include dry mouth, sedation, dizziness, and increased appetite. Some may also cause contact dermatitis when being applied to skin.[11] First generation H1-receptor inverse agonists are moderately lipophilic molecules and therefore they easily cross the blood-brain barrier, causing sedation and cognitive impairment.[12] The 2004 study of Kar Ng et al. on the effects of antihistamines on children showed that chlorpheniramine, a first generation antihistamine, increased significantly P300 latencies, an index of impaired cognitive function.[12,17] There have been a number of methods to assess the sedative effect such as psychomotor performance (monitoring of driving errors), sensorimotor co-ordination speed (dynamic visual acuity, pupillary light response), information processing (choice reaction time) as well as physiological measures and subjective rating scales (seft-rating of daytime sleepiness).[7,17] Through a double-blind study conducted on three experimental groups of young adults (one placebo group and two groups with different doses of d-chlorpheniramine) to investigate the effects of first generation H1-antihistamines on postural control, Yasuhiro Chihara and co-authors found that these drugs impair the neural pathways which play important roles in visual and vestibular activities.[18]

Common features
Most of widely used first generation H1-antihistamines are in the piperazine and piperidine class.[11] Some of them have their structures shown in the figures below. Loratadine (Claritin), compound **6**, is an allergic medication for rhinitis, urticaria, runny nose.[19] Its active metabolite, desloratadine (Clarinex), compound **7**, is a third generation H1-antihistamine.[20] They are different from each other only by the COOC2H5 group. (Figure 5) Cetirizine (Zyrtec), compound **9**, is a major metabolite of hydroxyzine, compound **8**, a first generation antihistamine. It is a D-stereoisomer (L-stereoisomer is levocetirizine, compound **10**, a third generation antihistamine).[11] (Figure 6) First sold in 1985, Terfenadine (Seldane), compound **11**, was the first non-sedating anti-allergy drug on the market. In 1992, it was discovered to have severe drug-drug interactions with the antibiotic taken by people with liver disease.[21] (Figure 7) Ebastine (Kestine) is another member of piperidine class for treating rhinitis and urticaria. Bilastine (Bilaxten): a novel non-sedating antihistamine for the treatment of rhinoconjunctivitis and urticaria. It is also effective for treating nasal and eye symptoms.[22,23]

Efficacy
Unlike first generation, the second generation antihistamines have been studied extensively with a great number of randomized, double-blind, placebo-controlled clinical trials.[11] With the structure having multiple aryl rings, the second generation H1 antihistamines have better binding affinity to H1 receptor. **9**, one of the second generation drugs, has chirality at the carbon connecting aryl rings; therefore, it increases the potency of the drug.[11] In addition, the metabolic passage of **9** is not through the liver but ends up directly in urine, that is essential for understanding its effects.[16] A regular daily dose of bilastine, another second generation drug, was proved to be also safe and effective for patients with renal insufficiency.[23] According to the research by Simons, Tmax for the second generation antihistamines is quite similar to first generation. However, the effect of most second generation drugs lasts 24 hours or longer.[11]

Adverse drug reactions
Second generation antihistamines are large molecules and relatively lipophobic, so they do not easily penetrate into the CNS.[7] The use of logP in the research study of Walsh and coworker also showed the second generation H1-antihistamines have very high logP values, indicating a poor capacity to reach the CNS. They also have greater affinity for peripheral H1 receptors rather than CNS H1-receptors, making them unlikely to cause sedation.[7] For this reason, **9**, one of the second generation antihistamines, was approved by the Food and Drug Administration (FDA) for treating children under five.[12] Also, in some research on the effects of the second generation H1-antihistamines on postural control and driving performance, they were shown to have much fewer side effects on the people taking them.[18,24] However, very high lipophilicity of the second generation H1-antihistamines may cause some toxicity such as cardiotoxicity. Although most of these drugs appear to be free of any cardiovascular adverse effects, they should not be cautious to be used for people with heart problems.[10]

Common features
Third generation H1-antihistamines are either the active enantiomer (10) or metabolite (7, 12) of the second generation drugs. They used to be listed as second generation, but they are now moved to third generation because of having greater efficacy and fewer side effects.

Efficacy
The third generation H1 antihistamines inherited all the advantages of the second generation. Therefore, they have a good binding affinity to H1 receptor. **7** is the one having the greatest binding affinity for the H1-receptor. According to the study by Devillier and co-authors, the binding affinity of **7** is over 50 times higher than that of **6** and **9**.[20] The terminal elimination half-life (t1/2) is an alternative measure of duration of action. The t1/2 of **7**, **12**, and **10** are about 27, 13, and 8 hours respectively.[20]

Adverse drug reactions
Third generation H1-antihistamines also have fewer side effects than the previous generation. They were reported to have no significant effect on cognitive or driving performance. Another good aspect of third generation is that they are generally free from drug-drug interactions.[20]

Comparison of three generations of H1-antihistamine
In general, most H1-antihistamines are rapidly and completely absorbed following oral administration, and within 4 hours, plasma concentrations achieve the maximum value.[10] Most of the first generation H1-antihistamines have only two aryl rings, causing low binding affinity to H1 receptors compared with the second and the third generation of H1-antihistamine which usually have three to four aryl rings.[11] In addition, first generation H1-antihistamines do not have chirality in the carbon atom connecting two aryl rings; as a result, the drugs do not have a good potency.[11] In the study of Simons on the second generation of H1-antihistamines, they were shown to outperform the first generation drugs when used in the treatment of rhinoconjunctivitis, urticaria, and asthma. In addition, elderly patients eliminate H1-antihistamines more slowly than young adults. The second-generation antihistamines cause fewer adverse effects in the elderly then first generation.[7] In the clinical study of Mansfield and co-authors using the Test of Variables of Attention (TOVA) to evaluate the side effects of taking **2**, a first generation drug, and **12**, a third generation one, the results revealed that **2** caused an increase in drowsiness while **12** had no significant effect.[25] In a similar study, Wilken and his coworker showed that although **2** and **7** have very similar efficacy for rhinitis treatment, **2** impaired CNS functioning (i.e. vigilance and cognition).[26] In a study on driving performance, the first generation antihistamines significantly reduce driving performance while the effects of second generation antihistamines on driving performance may or may not be present depending on the dose, sex, and time interval between testing. The third generation antihistamines were reported to have no effects on driving performance.[24] The third generation H1-antihistamines have greater efficacy and fewer side effects than second and first generation.[20]

Future approaches of antihistamines
New H1-antihistamines will continue to be researched and developed for clinical use. Higher selectivity and less adverse side effects will continue to be the goal. However, novel H1-antihistamines may not have superior efficacy to the old ones, but they may have fewer side effects than their ancestors.[25,26] In the future, the use of molecular techniques will also be applied for the design of more clinically advantageous H1-antihistamines; moreover, other histamine receptors H2, H3, or H4 will also be considered to be potential targets for allergic treatment.[27]

Conclusions
There has been an increase of research and development in the treatment of allergic diseases in recent years. With just a few modifications in the structures of the previous generations of H1-antihistamine, many novel drug molecules has been discovered and approved for clinical use to treat allergic diseases. From older generation to newer generation, there are always improvements either by enhancing the efficacy through the binding affinity to the receptor or reducing the side effects. The first generation antihistamines have low binding affinity to H1 receptor while the second and the third generation compounds have improved their binding affinity. Moreover, unlike quite small molecules of the first generation, with more bulky structures due to more aryl rings, the second and the third generation H1-antihistamines are prevented from penetrating into the CNS so that the sedative effects are lessened. The third generation antihistamines are proved to outperform the previous generations thanks to their high binding affinity to H1-receptor, free drug-drug interactions, and having fewer side effects. However, more studies need to be conducted to investigate the possibility of toxicity of those large drug molecules. This research study gave a broad view of the whole H1-antihistamine world so that new directions can be planned to develop and build many more drug molecules that are efficacious and free of reverse effects. In the future, the use of molecular techniques in drug design as well as the development of H2, H3, and H4 antihistamines would become very potential directions.

Reference
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