Does Over-the-Counter Purchase of Antihistamines by Residents of Dhaka City, Bangladesh Align with the Prescribing Choices of the Physicians Practicing in That City?

Most current guidelines recommend prescribing second-generation antihistamines (SGAs) over rst-generation antihistamines because SGAs are less likely to cause sedation and impairment of heavy work performance. However, common residents who use these antihistamines as over-the-counter (OTC) medicines are less likely to know that. So, this study was designed to compare the over-the-counter use of antihistamines by common residents with the prescribing preferences of physicians residing at Dhaka City, Bangladesh. Between June and August of 2017, a total of 100 Physicians from some of the top medical institutions of the city and 350 randomly selected common residents were directly interviewed with two separate semistructured questionnaires specically designed for each population. Data was statistically analyzed using Fischer’s exact test, Spearman’s rank correlation test and Kendall’s tau rank correlation test. e data shows that physicians prefer second-generation antihistamines with fexofenadine (48.09% of the total responses), desloratadine (16.03%), and rupatadine (13.74%) taking the top spots. Cetirizine (29.46% of total responses), desloratadine (14.73%), and chlorpheniramine (14.52%) were the most used OTC antihistamines by the common residents. Statistical analysis with Fischer’s exact test revealed that the di¢erence in preference of rst-generation antihistamines between physicians and common residents were extremely signicant ( < 0.0001). Furthermore, cetirizine (which is known to have some degree of sedating activity) and chlorpheniramine are more preferred among common residents than among physicians (extremely signicant di¢erence, < 0.0001 in both cases). e study concludes that physicians of Dhaka City are complying with practice guidelines, but sedating antihistamines still retain some popularity among the common residents. Hence, a more engaging community pharmacy is needed to minimize adverse e¢ects that can arise from OTC use of sedating antihistamines.


Introduction
Bangladesh is a developing country with a very high population density. As a consequence, it has been di cult to provide the best healthcare to the mass. However, the pharmaceutical sector of the country is quite advanced and has been able to ful ll the country's need of medicines [1]. is has created another problem, as the wide availability of medicines has prompted the common people and sometimes the physicians to unnecessarily resort to certain medicines [2,3]. is is further complicated by the lack of awareness about the dangers that accompanies unsupervised use of medicines. Recently, regulations have been developed to battle the indiscriminate use of medicines, but they are yet to be enforced e ectively [4].
Antihistamines are a class of drugs which are commonly taken by the common residents as over-the-counter (OTC) medicine. ese drugs are also frequently prescribed by physicians for colds and various types of allergic conditions. Antihistamines are generally considered to be safe, and are recognized as OTC medicine in most parts of the world. However, among the two classes ( rst-generation and second-generation) of antihistamines available in the market, the first-generation antihistamines (FGAs) can possess some risks to the patients due to their sedative property.
Multiple research organizations and medical practitioners' networks now recommend the use of second-generation antihistamines (SGAs) as the first choice in place of FGAs. In 2009, a joint initiative consisting of the European Academy of Allergology and Clinical Immunology (EAACI), Global Allergy and Asthma European Network (GA 2 LEN), European Dermatology Forum (EDF), and World Allergy Organization (WAO) made a recommendation that FGAs should not be used for urticaria and other allergic disorders and that recommendation was kept in the revised guideline published by the joint venture [5,6]. In 2010, GA 2 LEN published a position paper which actually recommended that FGAs should no longer be available as OTC products due to their various side-effects and availability of better alternatives (SGAs) [7]. e American guideline developed by Joint Task Force on Practice Parameters (JTFPP) consisting of the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) has similar recommendations giving emphasis on SGAs over FGAs [8]. e World Health Organization (WHO) and Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines also recommends SGAs [9]. In all instances, the main concern has been the sedative effect of FGAs and its consequences. Studies have shown that FGAs can disrupt REM (Rapid Eye Movement) sleep and impair cognitive function [10]. Furthermore, it also impairs the user's ability to perform heavy work and the ability to drive [11].
is work describes a survey-based study initiated to identify which antihistamines are being commonly taken by residents as OTC medicines and which are commonly prescribed by the physicians at Dhaka City of Bangladesh. Such information can be used to understand if the patients are taking antihistamines which possess greater risks to them. It would also allow the evaluation of the physician's role in the usage pattern of antihistamines by common residents who purchase it as OTC medicine.

Survey Questionnaire Preparation.
Survey questionnaire had to be prepared to collect data from two distinct populations namely the common people living in Dhaka City and the physicians who practice at the city. Consequently, two different survey questionnaire forms were prepared specifically to serve the purpose. e questionnaires were semistructured in nature so that a more robust statistical analysis could be performed but at the same time the respondents would be free to express their own opinions regarding the question asked. e questionnaire directed towards the common people was designed to learn about the actions taken by respondent when he/she contracted diseases like allergies and colds, the choice of antihistamine for such diseases, and the side-effects observed by the respondent. e questionnaire directed towards the physicians contained questions such as which class of antihistamines are more commonly prescribed by them, which side-effect is most concerning to them, and whether they support self-medication of antihistamines.

Data Collection.
Data was collected from various locations within Dhaka City, Bangladesh between June and August of 2017. Physician's data were collected by direct interview from doctors working at top medical institutions of the City including Dhaka Medical College and Hospital, Shaheed Suhrawardy Medical College and Hospital and Sir Salimullah Medical College and Hospital. Physicians in the field of General Medicine, Obstetrics and Gynecology, and Surgery were purposively selected as they are expected to prescribe them. For the collection of data from common residents, respondents were directly interviewed by the surveyor who was trained to interpret the brand names because common residents are less likely to recognize generic names.

Ethical Review.
is study was conducted in accordance with the Declaration of Helsinki (2000)  Oral consent was obtained from all individuals prior to data collection.

Statistical Analysis.
Collected data was tabulated by simple spreadsheet analysis. e data obtained from physicians and common residents was compared and the differences were evaluated using nonparametric tests namely the Fischer's exact test.
e Spearman's rank correlation coefficient and Kendall's tau rank correlation test were used as a nonparametric measure of rank correlation between the choice of antihistamine among physicians and common residents. All analysis was performed in GraphPad Prism (version 7.00) except determination of Kendall's tau which was done using Minitab (version 8.0).

Survey of Physicians.
Physician survey was conducted on a total of 100 reputed physicians practicing at Dhaka City. Among them 59% were General Medicine specialists, 13% were Surgeons, and 22% were Obstetricians and Gynecologists. 90% of the participating physicians had more than 2 years of experience. It was observed that 95% of the surveyed physicians commonly prescribe antihistamines. Data shows that 76% of the surveyed physicians prescribe nonsedating antihistamines for most occasions whereas only 4% mostly prescribe first-generation antihistamines. Among the antihistamine molecules available in Bangladeshi Market, according to the survey the top choice of the physicians was fexofenadine (used by 66.32% of the total number respondents) followed by desloratadine (22.11% of the total number respondents), and rupatadine (18.95% of the total number respondents). Figure 1 shows the data in terms of both the total number of respondents and the total number of responses. e survey also revealed that physicians consider sedation to be one of the most concerning side-e ects of antihistamines ( Figure 2).

Survey of Common Residents.
e survey of common residents was conducted on 350 randomly selected individuals residing at Dhaka City. Most of these individuals were literate and came from middle-income families. One of the goals of the survey on common residents was to evaluate the extent of self-medication and the data shows that 71.14% of the respondents resorted to self-medication and only 22% went to physicians for consultation for cold or allergies.
In this survey, the top antihistamine of choice was cetirizine, followed by desloratadine, and chlorpheniramine. Some other nonsedating antihistamines such as fexofenadine, and rupatadine were also mentioned ( Figure 3). It appears that personal preference (41.37% among the respondents who went for self-medication) is one of the most important factor when selecting a speci c antihistamine for self-medication. But some (6.43% among those who self-medicated) sought help from family members who are healthcare professional when selecting a speci c antihistamine. Only a fraction (17.27% of those who self-medicated) are using previous prescriptions to select the antihistamine for self-medication ( Figure 4).
In case of side-e ects, three-quarters (72.7%) of the respondents who answered the question reported sedation ( Figure 5). But it should also be mentioned that almost 40% did not report any side-e ects (i.e. did not answer the question).

Statistical Comparison.
When comparing the survey data from physicians and common residents, the choice of antihistamines in the two groups was one of the most interesting aspects. Nonparametric tests were used to determine if their choices are correlated or not. When performing these tests, only the choices that garnered a minimum of 5% response from either population were considered. e Spearman's rank correlation coe cient ( ) was found to be 0.086 indicating there is no correlation at all but the validity of this inference was statistically limited ( = 0.919). Similar observation was made with Kendall's tau rank correlation test ( = 0.067, = 1).
To study this dissimilarity between the two survey populations, the responses from the participants were grouped into two categories namely "sedating antihistamines" and "nonsedating antihistamines". en, a two-sided Fischer's exact test was performed to determine whether any signi cant di erence existed between the physicians and general public in terms of selecting sedating or nonsedating class of antihistamine. At 95% con dence interval, the -value was less than 0.0001 indicating extremely signi cant result. is indicates that there is statistically signi cant di erence in the choice of antihistamine class between physicians and the general public.
A test was also performed to see whether there is any signi cant di erence in the popularity of chlorpheniramine between physicians and common residents and it was found that the di erence was extremely signi cant ( -value <0.0001). Similar result was obtained when the test was repeated with cetirizine ( -value <0.0001).    Respondents were asked to name the antihistamines they normally purchase when a prescription is not available. Multiple responses were allowed for the question and therefore, the percentage is calculated based on the total number of responses as well as the total number of respondents.  Physicians were asked to mention the sidee ect which of the greatest concern to them, multiple responses were allowed, hence the percentage is calculated based on the total number of responses as well as the total number of respondents. products as well [12]. Regardless of the original intentions behind the petition, various economy models showed that this actually reduced the overall cost of therapy by reducing the incidences of side-e ects [12]. e main side-e ect of concern for healthcare professionals has been the sedative property of this class of drugs. Sedation may be bene cial for some patients, but it renders

Discussion
Antihistamines are commonly used by patients to revceive relief from allergic symptoms. In the USA, only rst-generation antihistamines were available as over-the-counter product till 2001. A citizen petition motivated the Food and Drug Administration to make several SGAs available as OTC  the physicians prescribing it. Cetirizine is a second-generation antihistamine which has been a popular choice during the years 2000s. Cetirizine has been found to impair performance to some degree in some studies, although at a lower extent compared to FGAs [10,15,19,20]. Nevertheless, it has higher sedation potential compared to other second-generation antihistamines. So, it is interesting to see that only 10.53% of the surveyed physicians (7.63% in terms of total responses) are prescribing cetirizine, but 40.80% (29.26% in terms of total responses) of the common residents prefer it.
A potential factor that could had explained common residents' choice of purchasing sedating antihistamines like FGAs and cetirizine was their use as sleep aids. However, no antihistamine is approved in Bangladesh for use as a sleep aid. In fact, as the data in Figure 5 shows, 72.77% of the respondents consider sedation to be a concerning side-effect, which in the opinion of the authors, is indicative that the respondents do not view them as sleep aids. Furthermore, advertising or promoting medicines in a public platform is strictly prohibited in the country. Hence, the choice of antihistamines could not be significantly affected by those factors.
is study is not without some limitations, most importantly the small sample size, especially when surveying the common residents. Another thing to note is that multiple answers were allowed for various questions asked in the survey. is made statistical analysis of the data more complicated. However, it is the belief of the authors that allowing multiple answers was necessary to reflect real-life situation specially for the physician survey.
e study shows that the physicians practicing at Dhaka City have moved away from first-generation antihistamines and prefer to prescribe antihistamines which have nearly zero potential to cause sedation and other effects on the central nervous system. On the other hand, common residents who are using antihistamines over-the-counter are still continuing to use molecules which have some degree of sedative activity. Since the common residents are usually not using to the advice of healthcare professionals to select an antihistamine for over-the-counter purchase, it may take some time before the market makes a complete move to nonsedating antihistamines.

Conclusion
Sedating antihistamines i.e. first-generation antihistamines are no longer recommended by healthcare networks and guidelines due to the risks associated with impaired performance in physical activities like driving and heavy work caused by these drugs. At Dhaka City, which is the center of healthcare profession in Bangladesh, physicians are showing very good compliance with those guidelines. However, a fraction of the common residents still continues to use those sedating antihistamines over-the-counter. erefore, the city requires more stringent practice of community pharmacy where skilled pharmacists would be available to provide the common residents with necessary advice regarding the use of antihistamines. them unable to perform work that requires psychomotor competency such as driving or li ing heavy objects. A study evaluated the impact of FGAs in aviation accidents and discovered that FGAs were found in 11% of the accidents in 2004 [7]. Various studies have also shown that FGAs tend to significantly impair driving performance, and perhaps some second-generation agents (e.g. Cetirizine and Loratadine) cause some degree of impairment as well [10,11,[13][14][15]. One study found that patients using FGAs have 1.61 times the risk of traffic accident compared to nonusers but the significance of the finding was statistically limited [16].
Consequently, reduced use of FGAs by both physicians and common residents may hold some benefits in healthcare and society. is study has found that physicians practicing at Dhaka City have largely moved away from FGAs with only around 5% of the physicians still prescribing those. However, a significant percentage of the common residents is still using FGAs (30.29% of the total respondents, 21.98% when considering the total number of responses rather than the respondents). A study conducted in Germany back in 2011 showed that while nearly half of the participating physicians use SGAs, 23% physicians were still prescribing FGAs [17]. So, the results obtained here is quite impressive.
It is also encouraging to see that physicians consider sedation to be one of the most concerning side-effects of antihistamines.
is may have contributed to their preference of SGAs. A large fraction (44.29% in terms of total respondents) of the surveyed common residents also experienced sedation as the main side-effect. Regardless, the reason why FGAs specifically chlorpheniramine are still being used may be that the price of these drugs are lower compared to available SGAs. e prices of some FGAs and SGAs are listed in Table 1. Since chlorpheniramine is 5 times cheaper than the cheapest SGA available in the country, it makes sense that it has some degree of popularity among the common residents. For anyone interested, they can visit the official website of Directorate General of Drug Administration (DGDA) of Bangladesh, to look up the current prices [18].
Another important finding was that common residents are using cetirizine significantly more when compared with