Introduction

Antihistamines are among the most widely used medications worldwide. They are used to treat allergic rhinitis, allergic conjunctivitis, and urticaria, and are also included in medications for cough, fever, and insomnia. Based on their pharmacokinetic properties, chemical structure, and adverse-effect profile, H1 antihistamines are classified as either first- or second-generation agents.

Because of differences in their selectivity for H1 histamine receptors, which are abundant in the central nervous system (CNS), individual H1 antihistamines differ in their effects on the sleep-wake cycle, attention, memory, and learning. Such daytime effects are undesirable, particularly in actively working individuals. Therefore, selecting an H1 antihistamine that provides optimal therapeutic efficacy while minimizing adverse effects is important.

Histamine and Its Receptors

Histamine is a biogenic amine synthesized from the amino acid histidine by the enzyme L-histidine decarboxylase. It is synthesized and released by various cell types in the human body, including basophils, mast cells, platelets, histaminergic neurons, leukocytes, and enterochromaffin cells. Once synthesized, histamine is stored in intracellular vesicles or granules and is released upon stimulation. It acts as a mediator of numerous physiological processes by binding to histamine receptors located in various tissues.

Histamine receptors are classified into four subtypes: H1, H2, H3, and H4. H1 antihistamines are not structurally similar to histamine and therefore do not bind to the histamine-binding site on the receptor. Instead, they bind to alternative receptor sites, thereby preventing receptor activation. Consequently, these agents function as inverse agonists of the H1 histamine receptor and are more accurately described as H1 antihistamines rather than H1 receptor antagonists (1–3).

Brain Histaminergic System

Histamine is best known as a mediator released by mast cells and basophils during immediate hypersensitivity reactions. However, it is also an important endogenous neurotransmitter. Histamine-producing neurons in the CNS are located within the tuberomammillary nucleus of the posterior hypothalamus, from where they project widely throughout the brain. Morphologically, the histaminergic system resembles other biogenic amine neurotransmitter systems, such as norepinephrine and serotonin, with numerous projections extending from compact neuronal nuclei.

Within the CNS, histamine acts through H1, H2, H3, and H4 receptors and participates in a variety of physiological processes. H1 receptors are widely distributed throughout the CNS, with the highest density found in the frontal, temporal, and occipital cerebral cortex, limbic system, substantia nigra, hippocampus, and cerebellum. Although receptor distribution differs between sexes, H1 receptor density is generally higher in females across all brain regions.

Histamine plays an important role in regulating the sleep-wake cycle, attention, memory, learning, and appetite. In addition, the histaminergic system interacts with other neurotransmitter systems. Histamine modulates acetylcholine release by reducing cholinergic activity, activates serotonergic neurons, and influences the acquisition of emotional memories through the amygdala, particularly those related to fear. Histamine promotes wakefulness, as histaminergic neurons are relatively inactive during sleep but highly active during periods of alertness and attention. It also contributes to appetite suppression by inhibiting the release of norepinephrine, a neurotransmitter involved in appetite stimulation. Furthermore, histamine promotes oxytocin release under various physiological conditions, including childbirth and lactation (4, 5).

Blood-Brain Barrier and Antihistamines

The effects of antihistamines on the CNS depend on their ability to cross the blood-brain barrier and bind to H1 receptors within the brain. Their ability to penetrate the blood-brain barrier is determined primarily by the lipophilicity of the drug molecule and its affinity for P-glycoprotein (P-gp).

P-glycoprotein is a transmembrane transport protein located in the endothelial cells of cerebral capillaries. It regulates the transport of biologically active molecules, including hormones and xenobiotics, across cell membranes within the CNS. This transport is an active ATP-dependent process and occurs independently of concentration gradients across the cell membrane. Endothelial cells forming CNS capillaries are tightly connected and contain relatively few transendothelial channels, thereby limiting passive diffusion of soluble molecules. In addition to endothelial cells, the blood-brain barrier also consists of microglia, astrocytes, pericytes, and neurons.

First-generation antihistamines are highly lipophilic and have little affinity for P-glycoprotein, whereas second-generation antihistamines are less lipophilic and are good substrates for P-glycoprotein. Molecular weight alone does not determine blood-brain barrier penetration. For example, desloratadine (molecular weight 338.9 Da) and hydroxyzine (347.9 Da) have similar molecular weights, yet their penetration into brain tissue differs substantially. First-generation antihistamines have been shown to penetrate brain tissue approximately 5.5 times more readily than second-generation antihistamines.

Antihistamines are classified as non-sedating CNS agents based on three criteria: (1) the subjective absence of drowsiness following administration; (2) objective assessments demonstrating no impairment of cognitive or psychomotor function; and (3) positron emission tomography (PET) studies evaluating occupancy of central H1 receptors. The greater the occupancy of central H1 receptors, the greater the impairment of psychometric performance and brain function. An antihistamine is considered non-sedating if, at the maximum recommended therapeutic dose, central H1 receptor occupancy does not exceed 20%. Clinically significant CNS sedation generally occurs when more than 50% of H1 receptors are occupied, although some authors suggest that sedation becomes apparent only when receptor occupancy reaches 60% or even 70%.

The latter two criteria are particularly important. However, all three should be considered when classifying an antihistamine as a non-sedating CNS agent.

First-Generation Antihistamines and Their Effects on the CNS

First-generation antihistamines are synthesized from the same chemical groups as cholinergic antagonists, tranquilizers, antipsychotics, and antihypertensive agents. As a result, they have relatively low selectivity for H1 receptors and frequently interact with receptors for other biogenic amines, producing antimuscarinic, anti-alpha-adrenergic, and antiserotonergic effects. These agents readily interfere with histamine binding to H1 receptors in the CNS, leading to drowsiness, sedation, somnolence, fatigue, impaired cognitive function, memory deficits, and reduced psychomotor performance. Furthermore, their CNS activity is responsible for the potentially life-threatening toxicity associated with overdose.

First-generation antihistamines significantly alter the sleep-wake cycle. Studies have shown that, even at recommended therapeutic doses for allergic diseases, they commonly cause drowsiness, dizziness, sedation, daytime fatigue, and impaired memory and concentration. However, the absence of subjective drowsiness does not necessarily indicate that driving ability remains unimpaired. Subjective sleepiness and actual driving performance do not always correlate. Some individuals report no noticeable side effects despite measurable impairment of psychomotor function, whereas others experience drowsiness but perform normally on psychomotor testing.

During sleep, first-generation antihistamines prolong the time required to enter rapid eye movement (REM) sleep and reduce the overall duration of REM sleep. Because many of these agents have relatively long half-lives, residual effects often persist into the following morning, including impaired attention, reduced alertness, diminished working memory, sensorimotor impairment, and increased daytime sleepiness.

The sedative effects of first-generation antihistamines occur even at the lowest therapeutic doses. Certain groups are particularly susceptible, including women, older adults, and patients with hepatic impairment, renal insufficiency, or CNS disorders. Older adults are especially vulnerable to adverse effects, with these medications being associated with an increased risk of confusion and impaired speech, consciousness, and alertness. Consequently, first-generation antihistamines should generally be avoided in elderly patients. Although some studies have reported the development of tolerance to sedation and psychomotor impairment, this does not occur consistently.

First-generation antihistamines also potentiate the adverse effects of alcohol on oculomotor coordination, cognitive function, and driving performance. Co-administration with alcohol produces greater CNS impairment than that observed with second-generation antihistamines. Moreover, studies have demonstrated that first-generation antihistamines impair driving performance to a greater extent than alcohol alone at the doses evaluated.

These medications also enhance the sedative effects of benzodiazepines. While this interaction may be beneficial when treating anxiety disorders or insomnia, it should be carefully considered in other clinical situations, and the potential risks should be weighed before prescribing first-generation antihistamines.

Because of their peripheral anticholinergic activity, first-generation antihistamines may also cause mydriasis, blurred vision, and dry mouth. These adverse effects can interfere with everyday activities, particularly driving.

Patients with allergic conditions such as allergic rhinitis often experience impaired learning and concentration, and these difficulties may be further aggravated by first-generation antihistamines. Such effects have not been observed with second-generation agents. In a study involving 1,834 students taking examinations, adolescents with untreated allergic rhinitis were 40% more likely to score one or more grades lower than healthy peers. Among students taking first-generation antihistamines, this risk increased to 70% (7, 12). Similar adverse effects on memory have also been demonstrated in adults (13).

Many patients self-medicate with over-the-counter first-generation antihistamines to treat allergies, fever, insomnia, or other conditions. Because many of these individuals regularly drive, the associated impairment of cognition and psychomotor performance is particularly concerning. Cognitive testing and real-world driving studies consistently recommend that drivers avoid first-generation antihistamines because of their significant adverse effects on alertness and driving ability (11).

Second-Generation Antihistamines and the CNS

As discussed previously, second-generation antihistamines are less lipophilic and are good substrates for P-glycoprotein, limiting their penetration across the blood-brain barrier. At therapeutic doses, they occupy only 10–30% of central H1 receptors (14). An antihistamine is generally considered non-sedating if, at the highest recommended therapeutic dose, it occupies less than 20% of H1 receptors in the brain.

More than 80 randomized, double-blind, placebo-controlled comparative studies using psychometric and neurophysiological testing have demonstrated statistically significant differences between first- and second-generation antihistamines with respect to psychomotor performance, attention, and reaction time (15).

The interaction between second-generation antihistamines and alcohol depends partly on whether the drug is metabolized by the hepatic cytochrome P450 system. Drugs metabolized through this pathway are more likely to potentiate the effects of alcohol. Unlike first-generation agents, second-generation antihistamines generally do not enhance benzodiazepine-induced sedation, making them suitable for patients receiving benzodiazepine therapy (5).

Bilastine

Bilastine is a second-generation antihistamine with high selectivity for H1 receptors and minimal affinity for other receptor types, reducing the likelihood of off-target adverse effects. In addition, bilastine is an efficient substrate for P-glycoprotein, which limits its passage across the blood-brain barrier and results in minimal CNS effects (16).

The recommended therapeutic dose of bilastine for seasonal or perennial allergic rhinoconjunctivitis and urticaria is 20 mg once daily. At this dose, both subjective assessments and objective psychomotor test results are comparable to placebo. A 40 mg dose produced subjective drowsiness without impairing psychomotor performance, whereas only an 80 mg dose—four times the recommended therapeutic dose—resulted in measurable impairment on selected psychomotor tests (17).

Bilastine is not metabolized by the liver, eliminating the need for dose adjustment in patients with hepatic impairment or in older adults (9). It also does not interact significantly with alcohol.

A double-blind, placebo-controlled study evaluated the interaction between bilastine (20 mg and 80 mg) and alcohol (0.8 g/kg), comparing its effects with cetirizine 10 mg and hydroxyzine 25 mg. Although all comparator drugs impaired psychomotor performance, bilastine 20 mg combined with alcohol produced effects comparable to placebo and alcohol alone. Only the 80 mg dose of bilastine enhanced the effects of alcohol to a degree similar to cetirizine 10 mg and hydroxyzine 25 mg (Table 1) (18).

Another double-blind, placebo-controlled study evaluated the effects of bilastine on driving performance under real-world conditions. Single and repeated daily doses of bilastine (20 mg and 40 mg) for seven days were compared with hydroxyzine 50 mg as a positive control. Unlike hydroxyzine, bilastine did not impair driving performance at either dose after single or repeated administration. These findings indicate that bilastine does not adversely affect driving ability and can be safely used by individuals who operate motor vehicles (11, 19).

Overall, the available evidence supports bilastine as a non-sedating antihistamine with minimal CNS effects.

Table 1. Interaction of Antihistamines With Alcohol and Effects on Psychomotor Test Performance (18)

NS = not statistically significant. p<0.05 = statistically significant interaction.

Conclusion

Antihistamines are widely used to treat allergic rhinitis, allergic conjunctivitis, and urticaria and are also included in many medications for cough, fever, and insomnia. Based on their pharmacokinetic properties, chemical structure, and adverse effect profile, H1 antihistamines are classified into first- and second-generation agents.

Unlike histamine, H1 antihistamines are structurally different molecules that bind to alternative sites on the H1 receptor, functioning as inverse agonists rather than true receptor antagonists. Histamine itself is an important endogenous neurotransmitter produced by histaminergic neurons in the central nervous system, where it plays a key role in regulating the sleep–wake cycle, attention, memory, learning, and appetite.

The effects of antihistamines on the CNS largely depend on their ability to cross the blood-brain barrier and occupy central H1 receptors. First-generation antihistamines readily penetrate the CNS, where they interfere with histamine signaling and commonly cause drowsiness, sedation, somnolence, fatigue, impaired cognitive function, memory deficits, and reduced psychomotor performance. They also potentiate the CNS-depressant effects of alcohol and benzodiazepines.

In contrast, second-generation antihistamines have limited penetration into the CNS and produce little or no sedation at recommended therapeutic doses. They generally do not enhance the sedative effects of benzodiazepines and have a substantially lower impact on cognitive and psychomotor function.

Bilastine is a second-generation antihistamine with minimal CNS penetration. At recommended therapeutic doses, it does not impair cognitive or psychomotor performance, does not significantly interact with alcohol or benzodiazepines, and does not adversely affect driving ability.

Prepared by Dr. Neringa Buterlevičiūtė and Dr. Laura Malinauskienė
Center of Pulmonology and Allergology, Vilnius University Hospital Santaros Clinics