Allergic diseases are the most common chronic conditions lasting throughout the patient’s life. They not only cause significant deterioration in the quality of life of patients but also lead to significant absenteeism and reduced productivity, resulting in very high costs for society. Effective and safe treatment of allergic diseases is therefore one of the main challenges for public health and should be carried out by all the specialists in family medicine, internists and paediatricians in collaboration with allergists, otorhinolaryngologists and dermatologists. Antihistamines are most commonly used in the treatment of allergies. Several dozen drugs are available on the pharmaceutical market, and their generic forms are advertised widely as very effective drugs for the treatment of allergic diseases. What is the truth? What are the data from clinical trials and observational studies? Are all drugs equally effective and safe for the patient? According to a panel of experts representing various fields of medicine, inappropriate treatment of allergies can be very risky for patients, and seemingly equally acting medications may differ greatly. Therefore, a panel of experts gathered the latest data from the entire scientific literature and analysed the latest standards and recommendations prepared by scientific societies. This paper provides a summary of these studies and highlights the importance for the patient of the proper choice of drug to treat his allergies.
Which antihistamines should be chosen according to current standards and recommendations?
In the last few decades the incidence of allergic diseases has grown to epidemic status. According to the current data, more than 600 million people suffer from allergic rhinitis worldwide, approximately 25% of them in Europe. In the ECAP trial (Epidemiology of Allergic Diseases in Poland) as many as 30% of respondents reported allergic rhinitis, less than 7% mentioned urticaria, but over 40% of patients had positive skin tests with common inhaled allergens (e.g. plant pollen, dust mites, mould and animal hair). Despite this huge number of patients, these data are frequently underestimated, since allergic diseases are generally believed to be trivial and non-hazardous. However, it has already been proven that allergic rhinitis, asthma and urticaria are associated with a significant socioeconomic burden all over the world – regardless of region, development level and financial status. The total cost of allergic diseases brings both reduced quality of life and also direct costs of drugs and health services as well as indirect social costs such as the absence from work; it also decreases productivity and concentration and generates learning disorders and concomitant diseases. As allergic diseases occur mainly in the young population (which supports the senior population), their consequences are much more costly than those of diabetes, coronary heart disease or myocardial infarctions. In the USA alone, the costs of allergic rhinitis morbidity are estimated at over 25 billion dollars per year, of which approximately a half consists of indirect costs, resulting from insufficient disease control. Antihistamine Drugs Essay. In light of these studies it is not difficult to notice multidirectional benefits from effective management of allergic diseases, which improve both the patients’ activity, productivity and quality of life and ultimately decrease the financial burden of healthcare systems. Efficient therapy of the most common allergic diseases is based mainly on oral antihistamines which are administered simply and, as a result, have the best compliance among the drugs recommended for the treatment of allergic rhinitis.
Histamine plays an important role in human physiology, influencing immunoregulation of the acute and chronic inflammatory response through 4 different types of receptors, called H1, H2, H3, and H4. Drugs classified in the first generation of antihistamines (sometimes called “classical” antihistamines) act non-selectively. Apart from all histaminic receptors they also block muscarinic, adrenergic (or adrenoreceptors) and dopaminergic receptors, causing cardiovascular, urinary and gastrointestinal adverse reactions. High lipophilicity and consequently easy crossing of the blood-brain barrier additionally intensify the most dangerous adverse events from the central nervous system, including drowsiness, decreased concentration, vigilance and psychomotor efficiency as well as reduced ability to learn and memorize, which is not related to sedation. However, in histamine-dependent allergic diseases the most important role is played by the H1 receptor, whose stimulation by histamine results in e.g. constriction of smooth muscles (obturation of inhalatory tract), increased permeability of endothelium (oedema) and stimulation of sensory nerves and cough receptors (pruritus, sneeze attacks, rhinorrhoea). Therefore, the discovery of compounds selectively acting on H1 receptors, currently called second generation drugs, could be considered the greatest breakthrough during more than 70 years of the history of antihistamines (Figure 1). Antihistamine Drugs Essay.On top of the high efficacy, the most important feature of these drugs is the incomparably better safety profile: some of them have the same (or even lower) number of adverse reactions as placebo. Due to the selective mechanism of action, low penetration of the central nervous system (CNS) and lack of interaction with adrenergic, muscarinic and dopaminergic receptors, the second generation drugs are devoid of the majority (if not all) of the side effects mentioned above; however, some of them could cause other serious adverse reactions, including body mass gain, inter-drug interactions or potentially life-threatening cardiotoxicity (in the majority of countries, these preparations have been withdrawn from the market) (Figure 2). Due to selective antagonism with H1 receptors, these drugs are highly effective in reduction of allergic rhinitis and urticaria symptoms, and the wide therapeutic index makes it possible to use them in very high doses without any concerns related to overdosing toxicity, which with the first generation drugs could lead to consciousness disturbances, coma, respiratory distress, and even death.
Development history of antihistaminic drugs
Adverse effects of antihistamines
The described characteristics and easy usage as well as affordable price led to the inclusion of the second generation antihistaminic drugs in all global and local recommendations as the drugs of choice in all forms of allergic rhinitis and urticaria. The most frequently cited are ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines, which discusses pharmacotherapy and presents the second generation anti-H1 drugs in the first place, recommending them in all adults and children [1]. Additionally, they highlight that the first generation drugs are not recommended wherever newer drugs are available. Antihistamine Drugs Essay. Almost the same recommendations could be found in the current EAACI/GA(2)LEN/EDF/WAO guidelines of urticaria management, in which non-sedative second generation antihistamines are recommended not only as the first but also as the second line drugs (after a maximum 4-fold dose increase in case of lack of efficacy of the standard dose administered for 2 weeks).
In light of the presented guidelines it is quite clear that non-sedative antihistamines are the backbone of allergic diseases treatment. However, the number of available drugs brings a dilemma: which drug should be chosen? Which criteria should be recognized in the decision-making process? Patients have different expectations, concomitant diseases and symptoms intensity, so the answer is not obvious, and each patient should be treated individually. From an average allergic perspective, the most important criteria of the drug choice are efficacy and price but – considering that not all second generation drugs are totally side effect-free in term of sedation, and their influence on ability to drive and learn is not commonly known by people – the safety profile and side effects should be especially taken into consideration in the drug selection process. Moreover, there are more and more patients in allergology practice treated due to concomitant chronic diseases, so inter-drug interactions are also an important factor, which should be taken into consideration treating allergic rhinitis and urticaria [2]. Thus, drugs which are not metabolized in the liver should be chosen.
As the second generation antihistamines available in Poland have comparable efficacy in controlling allergic rhinitis and urticaria symptoms, the most important factor distinguishing them seems to be the influence on the CNS and the safety of this therapy. Hence, when prescribing an anti-H1 drug according to recommendations we should first take into consideration the preparations with the smallest possible sedative effect, wide therapeutic index, beneficial pharmacokinetics and the lowest number of inter-drug interactions (Figure 3). This selection is of special importance in patients whose professions require concentration (such as driving), in which even a small sedative effect could lead to serious consequences (Figure 4). Here, we present the expert opinion regarding the role of bilastine in the management of allergic rhinitis and urticaria as a non-sedative second generation antihistaminic drug of an extremely favourable safety profile which does not influence the ability to drive vehicles and other machines, does not have any interactions with other drugs or alcohol, and (in allergic patients) decreases drowsiness even when compared to placebo [3, 4]. Antihistamine Drugs Essay.
Efficacy and safety of bilastine 20 mg compared with cetirizine 10 mg and placebo for the symptomatic treatment of seasonal allergic rhinitis (somnolence) [3]
Efficacy and safety of bilastine 20 mg compared with cetirizine 10 mg and placebo for the symptomatic treatment of seasonal allergic rhinitis (fatigue) [3]
The newest antihistamines in the management of allergic rhinitis and allergic conjunctivitis
Allergic rhinitis is a complex of clinical symptoms caused by an inflammatory reaction including antibodies immunoglobulins E (IgE) targeting sensitizing allergens. The clinical symptoms of allergic rhinitis include rhinorrhea, nasal congestion, itchy nose and sneezing [5]. These symptoms are recurrent and intensify after contact with the allergen. Sometimes the patient’s complaints include concentration disturbance, fatigue, or snoring.
Allergic conjunctivitis frequently coincides with allergic rhinitis. Eye symptoms, including watering, redness and itching, usually develop before nasal symptoms.
Allergic rhinitis and allergic conjunctivitis are concomitant so frequently that in many countries they are defined as one condition (e.g. allergic rhinoconjunctivitis).
The symptoms of allergic rhinitis significantly reduce quality of life; they adversely influence social life and decrease performance in learning and work. Untreated (or undertreated) allergic rhinitis (incompatible with recommendations) could lead to complications in the lower respiratory tract, paranasal sinuses and ears.
In the ECAP trial the incidence of allergic rhinitis was assessed and attributed to 22.4% of the population under research [6]. Antihistamine Drugs Essay.
According to triggering allergens and duration of exposure time, allergic rhinitis was previously divided into seasonal, perennial and occupational. In 2001, an international workgroup proposed an ARIA statement with a new classification of allergic rhinitis based on duration of clinical symptoms. They distinguished periodic allergic rhinitis (with symptoms not shorter than 4 days per week or shorter than 4 weeks) and chronic allergic rhinitis (with symptoms lasting for more than 4 days per week and longer than 4 weeks) [5]. Depending on the intensity of symptoms, allergic rhinitis could be split into mild and moderate/severe.
The choice of drugs for allergic rhinitis treatment is based on its intensity level and clinical symptoms. In each case, allergen-specific immunotherapy should be considered.
Updated recommendations indicate that the second generation antihistamines (without a sedative effect) and local glucocorticosteroids are the main drugs used in allergic rhinitis management. Although the second generation antihistamines reduce itching and sneezing highly efficiently, glucocorticosteroids effectively reduce nasal congestion, which is a symptom of delayed allergic reaction.
According to the recommendations published in ARIA and PoSLeNN (Polskie Standardy Leczenia Nieżytów Nosa) documentation, the basic treatment of patients with any form of chronic allergic rhinitis as well as in moderate and severe periodic allergic rhinitis should be based on local glucocorticosteroids [7, 8], and oral antihistamines should complement allergic rhinitis therapy. Antihistamine Drugs Essay. The use of oral antihistamines is specifically justified in patients with concomitant extra-nasal symptoms: pruritus, eye watering and redness, symptoms from the mouth and pharyngeal mucosa as well as skin signs. The second generation oral antihistamines are indicated, including those without a sedative effect. Allergic rhinitis involves the nasal cavity, and it is also a systemic disease, so the systemic treatment would relieve all relevant symptoms of allergic inflammation.
The nasal cavities should be investigated before local administration of glucocorticosteroids. In the case of very tight nose congestion local drugs are ineffective because they could not be delivered to the entire nasal mucosa. Patients with anatomical variations (e.g. nasal septum deviation, hyperplasia of nasal turbinate) have additional restrictions with administration of intranasal drugs. Treatment with intranasal glucocorticosteroids could be associated with adverse reactions (burning sensation, pain, bleeding) which could discourage patients from taking such drugs. The full effect of the drug could be apparent at 5–7 days of its administration; however, the relief of symptoms could be observed within a few hours after the administration of the second generation antihistamines. This is very important in patients with periodic allergic rhinitis, when the duration of the condition is shorter than the onset of action of intranasal glucocorticosteroids. Physicians and patients are also discouraged by the quite widespread phobia of steroids. For these reasons, many patients prefer to use oral drugs instead of intranasal drugs. Therefore, the therapy with the second generation antihistamines seems to be more beneficial. Favourable tolerability and safety profile of the drug should always be considered when taking a decision on the choice of an antihistamine. Bilastine is the most modern drug in this group, and meets the criteria mentioned above.
In a randomized, double-blinded, placebo-controlled clinical trial Horaka et al. [9] compared in Vienna Challenge Chamber conditions outside the pollen season the efficacy of bilastine, cetirizine and fexofenadine in relieving nasal and extra-nasal (mainly ocular) symptoms of allergic rhinitis. They found that bilastine in a dose of 20 mg is effective in relieving the nasal and extra-nasal symptoms of seasonal allergic rhinitis. Bilastine is characterized by fast onset of action already at one hour after administration, and the effect lasted over 26 h. Bilastine is more effective when compared to placebo in relieving allergic rhinitis symptoms, and its efficacy in relieving the nasal symptoms of allergic rhinitis was comparable with cetirizine. Compared to fexofenadine in the dose of 120 mg, bilastine in the dose of 20 mg is significantly more effective in relieving nasal symptoms of seasonal allergic rhinitis in the period between the 22nd and 26th h after its administration. Antihistamine Drugs Essay.
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In another randomized, double-blinded clinical trial, the efficacy of bilastine in the dose of 20 mg and cetirizine in the dose of 10 mg was compared with placebo in 681 patients from 61 European sites [3]. The results showed that bilastine in the dose of 20 mg administered once a day for 2 weeks was more effective than placebo in relieving the symptoms of seasonal allergic rhinitis. Bilastine showed the same efficacy as cetirizine in relief of nasal and extra-nasal symptoms of allergic rhinitis for the entire 14 days of treatment. Bilastine decreased the intensity of patient’s discomfort associated with allergic rhinitis comparably to cetirizine.
In a randomized, double-blinded, placebo-controlled clinical trial bilastine (20 mg), desloratadine (5 mg) and placebo were administered to 721 patients at the age between 12 and 70 years with seasonal allergic rhinitis [10]. It was found that bilastine administered for 2 weeks in a dose of 20 mg efficiently relieved the symptoms of seasonal allergic rhinitis. Additionally, bilastine significantly reduced the symptoms of allergic rhinitis as compared to placebo. Efficacy of bilastine and desloratadine in relief of nasal and extra-nasal symptoms of allergic rhinitis after 7 and 14 days was similar. Comparably to desloratadine, bilastine improved the quality of life in patients with allergic rhinitis.
In a randomized, double-blinded, placebo-controlled clinical trial Sastre et al. [11] compared the efficacy of bilastine and cetirizine in the treatment of allergic rhinitis. It was found that the efficacies of bilastine and cetirizine are similar and significantly higher when compared to placebo. Additionally, bilastine was found to be effective, safe and well tolerated in 12 months of treatment. Antihistamine Drugs Essay.
