Antihistamines for Allergic Rhinitis Treatment from the Viewpoint of Nonsedative Properties

Abstract

Antihistamines targeting the histamine H₁ receptor play an important role in improving and maintaining the quality of life of patients with allergic rhinitis. For more effective and safer use of second-generation drugs, which are recommended by various guidelines, a classification based on their detailed characteristics is necessary. Antihistamines for first-line therapy should not have central depressant/sedative activities. Sedative properties (drowsiness and impaired performance) are associated with the inhibition of central histamine neurons. Brain H₁ receptor occupancy (H₁RO) is a useful index shown to be correlated with indices based on clinical findings. Antihistamines are classified into non-sedating (<20%), less-sedating (20⁻50%), and sedating (≥50%) groups based on H₁RO. Among the non-sedating group, fexofenadine and bilastine are classified into "non-brain-penetrating antihistamines" based on the H₁RO. These two drugs have many common chemical properties. However, bilastine has more potent binding affinity to the H₁ receptor, and its action tends to last longer. In well-controlled studies using objective indices, bilastine does not affect psychomotor or driving performance even at twice the usual dose (20 mg). Upon selecting antihistamines for allergic rhinitis, various situations should be taken into our consideration. This review summarizes that the non-brain-penetrating antihistamines should be chosen for the first-line therapy of mild allergic rhinitis.

Keywords: H1 receptor occupancy; allergic rhinitis; antihistamine; bilastine; fexofenadine; non-brain-penetrating.

Figure 1

Early studies on positron emission tomography (PET) measurements of brain histamine H₁ receptor occupancy. These images show radioactivity in horizontal brain sections at the striatal level (upper) and the cerebellar level (lower) after intravenous injection of [¹¹C]doxepin into healthy volunteers. Terfenadine (60 mg), epinastine (20 mg), or d-chlorpheniramine (2 mg) was orally administered 1 h before the doxepin injection. For example, d-chlorpheniramine clearly decreased the accumulation of the [¹¹C]ligand in the brain, resulting in a histamine H₁ receptor occupancy of 76.8%. The brain histamine H₁ receptor occupancy (%) was defined and calculated as described [18]. Modified based on [18].

Figure 2

Brain histamine H₁ receptor occupancies of various antihistamines and classification for sedating actions. The occupancy data are represented as the mean ± SD of measurements in [¹¹C]doxepin-positron emission tomography after oral single-dose, eye drop (*), or intravenous (iv) administration of the drugs; the data were obtained by more than one research group. When H₁ receptor occupancy was 20% or lower, impaired performance was not observed in a simultaneously performed cognitive function test [19,21], and therefore, the drug could be classified as “non-sedating” (Modified based on [8]).

Figure 3

Chemical structures of several non-sedating antihistamines. There are two types of non-sedating antihistamines: the amino group type (epinastine and desloratadine) and the carboxy group type (the others; zwitterionic compounds). MW, molecular weight; (R), (S), optical isomers; (Z), geometric isomer; *, the carbon atom that is related to optical isomerism; #, the double bond that is related to the structurally different geometric isomer (cis-trans isomer) without optical isomerism. The carboxy group types are characterized by high specificity to H₁R, while the amino group types bind to other GPCR receptors such as muscarinic receptors. Note that the mean molecular weight of marketed CNS drugs is approximately 310 Da and that the molecular weights of fexofenadine and bilastine are larger than others.

Figure 4

A new classification of antihistamines based on brain histamine H₁ receptor occupancy. Antihistamines can be classified into non-sedating, less-sedating, and sedating groups based on the H₁RO and mean plasma concentration of the drugs measured during positron emission tomography, as previously reported [9,29]. In this figure, the concept of “non-brain-penetrating” [32] is included. The H₁ROs of non-brain-penetrating antihistamines are nearly zero and not correlated to the plasma concentrations of the drugs. The H₁ROs of non-sedating and less-sedating antihistamines, in the range of up to 20% (for non-sedating) or 50% (for less-sedating), are proportional to some degree to the plasma concentrations of the drugs and have increased brain penetration. Sedative antihistamines rapidly penetrate the brain and show 50% or more H₁RO, associated with increasing plasma drug concentrations. AH, antihistamines. (Modified based on [9].)

Figure 5

Acid–Base Dissociation Constant (pKa). Non-sedating antihistamines of the carboxy group type have zwitterionic properties with positive and negative charges at two sites. The pKa of bilastine and fexofenadine are nearly the same, and these drugs are mostly dissociated at the physiological pH, making them difficult to penetrate into the brain. Non-sedating antihistamines are not potent inhibitors of P-glycoprotein; therefore, they are considered not to penetrate into the brain because of complex reasons, including molecular weight and pKa.