Safety and impact of bilastin treatment on patients' quality of life

Introduction

Histamine is a biogenic amine that, acting through its receptors, causes the development of allergic disease symptoms such as allergic rhinitis and urticaria. There are four types of histamine receptors: H1, H2, H3, and H4. When histamine binds to the H1 receptor, it promotes the release of mediators involved in allergic reactions from mast cells and basophils, activates antigen-presenting cells, promotes the activation and proliferation of T helper 1 (Th1) cells, interferon production, cell adhesion molecule synthesis, eosinophils, and neutrophil chemotaxis [1]. These receptors are not only found on eosinophils, neutrophils, monocytes, dendritic cells, T and B lymphocytes, epithelial cells, endothelial cells, hepatocytes, respiratory, and vascular smooth muscle cells but also in the central nervous system (CNS), where histamine acts as a neurotransmitter [2]. Antihistamines are H1 histamine receptor inverse agonists, classified into older, first-generation, and newer, second-generation, antihistamines [3].

This article discusses the safety data of bilastine, the latest second-generation antihistamine, and the impact of bilastine treatment on patients' quality of life.

First and Second Generation Antihistamines

Background of First-Generation Antihistamines

Since the 1940s-1950s, first-generation antihistamines have come into use in clinical practice. These substances stem from the same chemical group compounds as anticholinergic drugs, tranquilizers, antipsychotics, and antihypertensive drugs. Having low selectivity, first-generation antihistamines often interact with receptors meant for other biogenic amines. These interactions lead to unwanted anticholinergic, anti-alpha-adrenergic, and anti-serotonin effects. Among other things, first-generation antihistamines easily cross the blood-brain barrier and bind to the H1 histamine receptors found on histaminergic neurons distributed throughout the CNS in postsynaptic membranes.

Side Effects of First-Generation Antihistamines

The binding to H1 histamine receptors results in a range of side-effects like drowsiness, sedation, fatigue, cognitive impairment, psychomotor dysfunction, and memory disturbances. These central nervous system effects can turn life-threatening if a patient overdoses on first-generation antihistamines[4]. Known for being lipophilic, rapidly absorbed, and metabolized in the liver by the cytochrome P450 system, first-generation antihistamines usually require administration 3-4 times a day and can interfere with other drugs metabolized by the cytochrome P450[2].

Limitations of First Generation Antihistamines

Despite the fact that first-generation antihistamines can help mitigate symptoms of allergic diseases, they do come with significant drawbacks. Notably, their sedative and anticholinergic effects can intrude on routine activities. These unwanted side effects can also elevate the risk of accidents in situations that necessitate alertness, such as when driving or operating heavy machinery. Moreover, the high levels of weakness, dizziness, and fatigue associated with these drugs can lead to patients not following medical advice as diligently as they should. Consequently, primarily because of their impacts on the central nervous system, healthcare professionals frequently advise against employing first-generation antihistamines for extended durations in the treatment of allergic diseases[3,4].

Introduction to Second-Generation Antihistamines

The 1980s saw the introduction of second-generation antihistamines that boast more favorable pharmacokinetics for the patient and fewer sedative effects. Being less lipophilic than their predecessors, these antihistamines do not cross the blood-brain barrier as readily and thus do not suppress the CNS as much.

Benefits of Second-Generation Antihistamines

Second-generation antihistamines are more selective for H1 histamine receptors, reducing unwanted effects on other biogenic amine receptors. Unlike their first-generation counterparts, these antihistamines do not interact significantly with other drugs, food, or herbal products[2,5]. Loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine, and bilastine are some of the examples of second-generation antihistamines.

Bilastine pharmacology

New Antihistamine Drug

Bilastine structurally sets itself apart from other antihistamine drugs. Neither an active metabolite nor an enantiomer of another antihistamine drug, bilastine shows a moderate to strong affinity for H1 histamine receptors in animal studies. Its affinity ranks three times higher than cetirizine and five times higher than fexofenadine. Even at high concentrations, bilastine selectively binds to H1 histamine receptors instead of other tested receptors including muscarinic M3, serotonin, alpha1-adrenoreceptors, beta2-adrenoreceptors, bradykinin, leukotriene D4, calcium receptors and other histamine receptors like H2, H3, H4[6,7].

Absorption and Metabolization of Bilastine

When taken orally, bilastine gets rapidly absorbed, reaching peak concentration in blood plasma in about one hour. The average biological availability of the drug is 61 percent. No drug accumulation is noted when administering repetitive therapeutic doses. Approximately 84–90 percent of the administered bilastine binds to blood plasma proteins[8,9].

Efficacy of Bilastine in Treatment of Allergies

Clinical trials involving over 4,600 patients have established the efficacy of bilastine in treating allergic rhinitis and urticaria. In these trials, investigators compared bilastine to placebo and other second-generation antihistamines. They found no statistically significant differences in treatment outcomes between bilastine and other second-generation antihistamines (cetirizine, levocetirizine, desloratadine)[10].

Safety and Tolerance of Bilastine

Bilastine's safety, adverse effects, and tolerability were evaluated in clinical trials. The data shows it is well-tolerated by patients with episodic and persistent allergic rhinitis and chronic urticaria. Adverse effects occurred at a similar frequency as in the placebo group, with no severe adverse effects or deaths reported. The most common adverse effects were headache, dizziness, fatigue, drowsiness[12–15].

Impact of Bilastine on Central Nervous System

Bilastine does not cross the blood-brain barrier and does not have a central nervous system depressant effect. In a double-blind placebo-controlled study, 20 mg, 40 mg, and 80 mg of bilastine were administered once daily for seven days. Objective changes in motor, cognitive, attention, and association integration functions were evaluated, as well as subjective mood changes.

Interactions of Bilastine with Alcohol and Other Medicines

Alcohol is known to enhance the drowsiness and impairment of psychomotor functions that first-generation antihistamines cause. In the case of bilastine, a double-blind placebo-controlled clinical trial was conducted to evaluate the interaction of bilastine (20 mg and 80 mg) with alcohol (0.8 g/kg), compared to cetirizine 10 mg and hydroxyzine 25 mg[20].

Impact of Bilastine on Cardiovascular System

The impact of bilastine on the cardiovascular system was evaluated according to the ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) E14 recommendations. Bilastine monotherapy at therapeutic and supratherapeutic doses did not affect T-wave morphology or QT interval (QTc) on electrocardiograms [22,23].

Impact of Bilastine on Quality of Life

Health-related quality of life indicators describe aspects related to the disease and its treatment from the patient's perspective. This indicator is subjective but important in assessing the economic and social burden of the disease. The impact of treatment with bilastine on the quality of life of patients with allergic rhinitis and urticaria was studied using special questionnaires. The patient's quality of life improved with bilastine treatment as it reduced discomfort caused by the disease [13,14].

The impact of treatment with bilastine on the quality of life of patients with chronic urticaria

Chronic urticaria impairs health-related quality of life similarly to atopic dermatitis, but more than psoriasis, common acne, vitiligo, or Behcet's disease [31]. When using general questionnaires and chronic urticaria it is compared to other diseases, a similar deterioration in the quality of life is determined as in patients with severe ischemic heart disease and those awaiting aortocoronary bypass surgery [32].

The first-line treatment for chronic urticaria is second-generation antihistamines. When comparing these drugs, no statistically significant differences were found in evaluating the control of chronic urticaria symptoms and improvement in quality of life [33]. The effect of Bilastine on the quality of life of patients with chronic urticaria was compared to levocetirizine.

Trials have shown that bilastine stands out as significantly more effective than a placebo in curbing itchiness, as well as reducing the amount and size of hives. It matches the effectiveness of levocetirizine in these aspects. When assessing changes in patients' quality of life, researchers noted improvements with both bilastine and levocetirizine. However, the difference between the two drugs was not statistically significant. Similarly, both drugs brought about a significant reduction in overall discomfort, as indicated by the Visual Analogue Scale (VAS), with no notable distinction between their effects [15]. These findings suggest that bilastine can markedly enhance the quality of life of patients battling chronic urticaria.

Summary

Bilastine is a second-generation antihistamine that, by its structure, is not similar to any other antihistamine, is not an active metabolite of another antihistamine, or an enantiomer. Its effectiveness has been proven in treating allergic rhinitis and urticaria.

Bilastine does not suppress the CNS, as it does not cross the blood-brain barrier. Furthermore, it does not enhance the sedative effect of alcohol and benzodiazepines, has no clinically significant interactions with other drugs. Bilastine does not prolong the QT interval and does not require dose adjustment in cases of hepatic and renal insufficiency.

In patients with allergic diseases, their quality of life worsens, and treatment with antihistamines, including Bilastine, significantly improves it in cases of allergic rhinitis and chronic urticaria.

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Author Neringa Buterlevičiūtė, Laura Malinauskienė, Vilnius University Hospital Santaros Clinic, Center for Pulmonology and Allergology

Article from the journal "Internistas"

LT/Ope/2014/09