Histamine is an important mediator of inflammation and is largely released by tissue mast cells, circulating basophils, and neurons as a result of both immunological and non-immunological stimuli, such as allergenic, inflammatory, toxic, chemical, and iatrogenic agents.

Discovered in the early 1900s by Sir Henry Dale, histamine is produced in the cytoplasm from the decarboxylation of histidine via the enzyme histidine decarboxylase; it has a short-term action (1–10min) and is rapidly degraded to imidazole acetic acid. Endogenous histamine is the main mediator of the immediate allergic response, participates in the regulation of gastric secretion (through the action of H2 receptors), and has immunomodulating activity.1 Moreover, histamine plays an important role as a neurotransmitter in the central nervous system (CNS), where it is catabolized by the enzyme histamine N-methyltransferase to tele-methylhistamine.2

Histamine performs its actions by binding to specific receptors on the membrane of various cells, such as mast cells, endothelial cells of the vessels, cells of sensitive nerve fibers, and bronchial smooth muscles, resulting in different effects depending on the site and type of receptor with which it interacts. To date, four types of histamine receptors have been discovered: H1, H2, H3, and H4, which belong to the superfamily of G protein-coupled receptors (GPCRs).3 The receptor activation causes various biological effects, including vasodilation, increased vascular permeability, itchiness, smooth muscle contraction, spasm of coronary arteries, and regulation of the sleep–wake rhythm.4 The current review will focus exclusively on H1 receptor and anti-H1 antihistamines.

The H1 receptor for histamine is in a dynamic equilibrium between two isoforms: active and passive. However, this receptor shows spontaneous basal activity via the nuclear factor κB (NF-κB).

NF-κB is a transcription factor involved in inflammation that has obtained a great interest as a drug target for the treatment of various allergic conditions. Histamine H1 receptor activates NF-κB in both a constitutive and agonist-dependent manner.5

Anti-H1 antihistamines cause an imbalance in favor of the isoform characterized by inactivity; they behave, in practice, as inverse agonists. An inverse agonist is a ligand that binds to the same receptor-binding site as an agonist and not only antagonizes the effects of an agonist but, moreover, exerts the opposite effect by suppressing spontaneous receptor signaling.6 As a result, they are capable of shifting the receptor balance from the biochemically active form to an inactive form. In this way, they also reduce the activation of NF-κB and thereby may reduce the synthesis of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors.1 Antihistamines are, therefore, a cornerstone in the treatment of histamine-mediated diseases.7

Anti-H1 antihistamines are functionally classified into two groups, namely first- and second-generation molecules (Table 1). First-generation anti-H1 antihistamines (e.g., clemastine, diphenhydramine, promethazine) can be administered by injection, orally, or topically, including dermatological, intranasal, and ocular formulation.7

After oral administration, most of them are well absorbed from the gastrointestinal tract; they bind to plasma proteins (70–97%) and are then metabolized by the liver and mostly excreted in the urine within 24h of intake. The therapeutic effect begins to appear within 30–60min, peaks within 1–3h, and usually persists for 4–6h. Some preparations, however, have a more prolonged effect (e.g., chlorpheniramine, hydroxyzine), with a half-life of over 20h in the adult, less time in the child, which metabolizes these drugs more quickly.1 The action mechanism is to bind to the H1 receptor, which in the first-generation molecules represents the prevalent or perhaps the only activity of the drug; it is perfected and expanded in the second-generation molecules.

In addition, for the second-generation molecules, there are different formulations, such as for oral use (e.g., drops, syrup, tablets) and for topical nasal, ocular, and cutaneous use. After oral administration, the plasma peak is earlier with cetirizine (30–60min) and later with loratadine (45–60min), terfenadine (1–2h), fexofenadine (1–3h), astemizole (1–3h), and bilastine (1–4h). The elimination half-life is extremely variable, from 24h for loratadine, desloratadine, cetirizine, and levocetirizine, up to 18 days for astemizole.1,3,4 In children, the cetirizine half-life is reduced due to increased hepatic metabolism; this practice entails the need for a twice-daily administration.8 The duration of the pharmacological effect of all these drugs presents a marked variability, and is much longer than the plasma half-life, being linked to the volume of distribution of the drug as well as to the action of the metabolites that also remain in active form for long periods. The binding of these drugs to plasma proteins is generally high (88–98%). From a clinical point of view, the therapeutic effect is, therefore, prolonged. The inhibition of the cutaneous response to histamine (histamine hives) persists for 12–24h after a single dose of loratadine and cetirizine9; the inhibitory effect on the skin response can endure for 7–10 days depending on the type of molecule taken. For this reason, antihistaminic therapy should be suspended before the skin prick test. Most second-generation antihistamines are metabolized in the liver by the cytochrome P450 system. The intake of some antihistamines, such as terfenadine or astemizole, together with drugs capable of inhibiting this system (e.g., anti-fungal agents such as ketoconazole or macrolide antibiotics) or some foods (e.g., grapefruit, pomelo, raspberry) can cause an abnormal accumulation of these agents and their metabolites in the body, with consequent risk of adverse reaction, even serious, especially at the cardiac level (e.g., tachyarrhythmias, torsade de pointes, or prolongation of the QT interval until ventricular fibrillation). These effects are not the result of the action on the H1 receptor but arise from the direct blockage of the potassium channels that control the cardiac repolarization phase. For this reason, terfenadine and astemizole were withdrawn from clinical use in many countries.

Other molecules, such as loratadine and desloratadine, are instead metabolized by more enzyme systems over the hepatic cytochrome P450 system, thus limiting the potential resultant clinical interactions. It is unlikely that multiple systems will be simultaneously inhibited with consequent accumulation of the molecule.10 Fexofenadine is minimally metabolized by the organism; its main route of elimination is by biliary excretion (approximately 80%), while −10% of the ingested dose is eliminated unchanged in the urine.1 About 60–70% of cetirizine and levocetirizine are eliminated via the urinary tract, with only 10% eliminated hepatically.11 Elimination is mainly fecal for astemizole, and fecal and urinary for loratadine.12 Furthermore, the binding of the new antihistamines with the H1 receptor is more stable and persistent; thus, the administrations can be more delayed over time and, for some molecules such as loratadine, desloratadine, cetirizine, levocetirizine, bilastine, fexofenadine and rupatadine, it is possible to use once-daily administration.3 These characteristics are particularly advantageous in clinical practice, as the reduced frequency of daily drug administrations consequently entails improvement of tolerability and compliance by patients and prolonged activity.11 It should also be noted that new antihistamines hold little or no risk of “pharmacological addiction” (tachyphylaxis) following long-lasting administration.3

Along with the antihistaminic effects, some second-generation drugs (e.g., loratadine, desloratadine, cetirizine, levocetirizine, ebastine, fexofenadine) were believed to have potential anti-inflammatory properties in the following manners: (1) reduction of the production of pro-inflammatory cytokines (e.g., IL-4 and IL-13, chemokines) and the release of both histamine and other pre-formed or neo-formed mediators by activated mastocytes and basophils; (2) reduction of the recruitment of eosinophils in the late phase of allergic reaction or the phase of tissue damage and chronicization of the allergic inflammation; and (3) reduced expression of adhesion molecules on epithelial cells and/or endothelium, thus inhibiting cellular trafficking.12,13 However, the anti-inflammatory activity of antihistamines has probably to be reduced because these effects would seem evident only in vitro at very high concentrations. Therefore, the anti-inflammatory activity of antihistamines administered at therapeutic doses seems to be scarcely relevant in clinical practice.

Currently, the clinical use of first-generation molecules is markedly limited by some of their pharmacological characteristics. Due to their high lipo-solubility, first-generation anti-H1 antihistamines can easily cross the blood–brain barrier (BBB) and induce sedation, drowsiness, decreased attention and reaction times, which comprise their most common side-effects.14 In this regard, a study about cerebral histamine H1 receptor occupancy (H1RO) using positron emission tomography (PET) has shown that the most penetrating antihistamines in the brain are chlorphenamine, ketotifen and hydroxyzine.15

First-generation anti-H1 antihistamines also exert a poorly selective action on H1 receptors because they can also interact with non-histamine receptors (especially serotonergic, cholinergic, and α-adrenergic receptors). As a consequence, the other main side-effects include dry mouth, nausea, vomiting, diarrhea, constipation, pollakiuria, dysuria, urinary retention, increased appetite, and tachycardia.14 Cyproheptadine and ketotifen can increase appetite and cause weight gain, which does not occur with other antihistamines (except sporadically by astemizole), mainly acting on serotoninergic pathways.16 Because of the unfavorable risk/benefit ratio due to relevant side-effects, first-generation antihistamines, if possible, should no longer be used in the treatment of rhinitis and urticaria.14 As regards the safety of these drugs, warnings have been issued, more recently in 2015, by the European Medicines Agency (EMA) on the use of first-generation anti-H1 for children under two years of age, especially for hydroxyzine. That drug is associated with a low but definite risk of QT tract prolongation and torsade de pointes, conditions that can lead to an abnormal rhythm until cardiac arrest.

For this reason, its use must be limited to the minimum effective dose for the shortest possible duration; it is also imperative to avoid its use in patients who present risk factors for heart rhythm disorders. Regarding the pediatric age, the maximum daily dose of hydroxyzine should not exceed 2mg/kg (maximum 50mg/day) in children weighing less than 40kg.17 Given their low lipo-solubility, the second-generation molecules have a reduced capacity to cross the BBB. These molecules are also able to bind to P-glycoprotein, which acts as a transporter at the BBB and can actively “expel” these molecules from the BBB.

Among the second-generation antihistamines, cetirizine appears to be most frequently associated with a greater incidence of drowsiness in comparison to placebo, although to a lesser extent than that observed with the use of first-generation antihistamines.18 However, this effect is less relevant in comparison with adult patients.

Antihistamine overdose remains a risk, especially in children. Historically, diphenhydramine has been involved in episodes of overdose poisoning (some fatal), especially in children, partly because many preparations are sold without a prescription (over-the-counter products).19 The most serious effects of overdose are attributable to neurological or cardiac alterations; for example, convulsions that are followed (at high dosages) by states of coma, which are sometimes irreversible.14 Some second-generation antihistamines, such as ebastine, or mizolastine can cause a prolongation of the QT tract. Considering this potential risk, particular attention should be paid to the simultaneous administration of other drugs that can also prolong the QT tract, such as macrolides, which are among the classes of drugs most frequently prescribed in pediatric populations.10

The main indications of anti-H1 antihistamines are allergic manifestations with prevalent exudative and irritative neurogenic features; however, the efficacy of antihistamines varies in different pathologies depending on the prominence of histamine's contribution to the clinical symptomatology and local health agency rules.11,18 Second-generation antihistamines should be preferred since they are endowed with few sedative properties. Treatment with a second-generation anti-H1 antihistamine (e.g., loratadine) in children suffering from allergic rhinitis did not impair scholar performance, unlike treatment with a first-generation molecule (e.g., diphenhydramine).14 Second-generation anti-H1 antihistamines also have the advantage, due to their pharmacological characteristics, of being used not only in the treatment of an acute episode but also in the long-term treatment of allergic diseases.20

The oral route is the main way of administration, while the parenteral route, which is only possible with some first-generation molecules, is reserved for the prevention or treatment of serious and rare eventualities (e.g., episodes of anaphylaxis, blood transfusions, adverse drug reactions). The topical route is reserved for eyes, nose, or cutaneous disease (eye drops, spray, cream, gel). The topical dermal route, despite having indications of insect bites and pruritic dermatitis, should be used with great caution as it commonly induces photosensitivity.21 A summary of the most common antihistamines is available in Table 2.

Anti-H1 antihistamines are frequently used in children and adolescents to treat allergic diseases. The effectiveness of second-generation antihistamines has been well studied, and they should be preferred to minimize adverse effects and to take advantage of their antiallergic activity. The choice of the preferred molecule should be based and individualized on the clinical and pharmacological characteristics of each subject.

The authors declare no conflicts of interest.

The authors did not receive any funding for the research.