Pharmacology of Antihistamines

Abstract

H_1-antihistamines, the mainstay of treatment for urticaria, were developed from anticholinergic drugs more than 70 years ago. They act as inverse agonists rather than antagonists of histamine H₁-receptors which are members of the G-protein family. The older first generation H_1-antihistamines penetrate readily into the brain to cause sedation, drowsiness, fatigue and impaired concentration and memory causing detrimental effects on learning and examination performance in children and on impairment of the ability of adults to work and drive. Their use should be discouraged. The newer second-generation H₁-antihistamines are safer, cause less sedation and are more efficacious. Three drugs widely used for symptomatic relief in urticaria, desloratadine, levocetirizine and fexofenadine are highlighted in this review. Of these levocetirizine and fexofenadine are the most potent in humans in vivo. However, levocetirizine may cause somnolence in susceptible individuals, whereas fexofenadine has a relatively short duration of action and may be required to be given twice daily for all round daily protection. Although desloratadine is less potent, it has the advantages of rarely causing somnolence and having a long duration of action.

Introduction

To understand H₁-antihistamines, it is necessary to appreciate the state of science in the 1930s. In his review about his own work,[1] Daniel Bovet wrote “Three naturally occurring amines, acetylcholine, epinephrine, and histamine, may be grouped together because they have a similar chemical structure, are all present in the body fluids, and exert characteristically strong pharmacologic activities. There are alkaloids which interfere with the effects of acetylcholine. Similarly, there are sympatholytic poisons which neutralize or reverse the effects of epinephrine. It seemed possible to me, therefore, that some substance might exist which exerts a specific antagonism toward histamine.” It was against this background that Bovet, who was looking for antagonists of acetylcholine, asked his student, Anne-Marie Staub, to test some of these compounds against histamine. This led to the discovery of the first H₁-antihistamine in 1937.[2] Although this compound was too toxic for use in humans, it opened the door for the introduction into the clinic of antergan in 1942,[3] followed by diphenhydramine in 1945[4] and chlorpheniramine, brompheniramine, and promethazine later the same decade.[5]

The histamine H₁-receptor

The histamine H₁-receptor is a member of the superfamily of G-protein-coupled receptors (GPCRs) [Figure 1a]. GPCRs may be viewed as “cellular switches” which exist as an equilibrium between the inactive or “off” state and the active or “on” state.[6] In the case of the histamine H₁-receptor, histamine cross links sites on transmembrane domains III and V to stabilize the receptor in its active conformation, thus causing the equilibrium to swing to the “on” position[7] [Figure 1b]. H₁-antihistamines, which are not structurally related to histamine, do not antagonize the binding of histamine but bind to different sites on the receptor to produce the opposite effect. For example, cetirizine cross links sites on transmembrane domains IV and VI to stabilize the receptor in the inactive state and swing the equilibrium to the “off” position[8] [Figure 1c]. Thus, H₁-antihistamines are not receptor antagonists, but are inverse agonists in that they produce the opposite effect on the receptor to histamine.[6] Consequently, the preferred term to define these drugs is “H₁-antihistamines” rather than “histamine antagonists.”

Figure 1.

(a) Diagram of a histamine H₁-receptor in a membrane showing seven transmembrane domains. Histamine stimulates the receptor following its penetration into the central core of the receptor. (b) A surface view of an activated receptor with histamine linking domains III and V. (c) A surface view of an inactive receptor with cetirizine linking domains IV and VI

The development of H₁-antihistamines

Bearing in mind that first-generation H₁-antihistamines derive from the same chemical stem from which cholinergic muscarinic antagonists, tranquilizers, antipsychotics, and antihypertensive agents were also developed, it is hardly surprising that they have poor receptor selectivity and often interact with receptors of other biologically active amines causing antimuscarinic, anti-α-adrenergic, and antiserotonin effects. But perhaps their greatest drawback is their ability to cross blood–brain barrier and interfere with histaminergic transmission. Histamine is an important neuromediator in the human brain which contains approximately 64,000 histamine-producing neurons, emanating from the tuberomammillary nucleus.[9] Stimulation of H₁-receptors in all of the major parts of the cerebrum, cerebellum, posterior pituitary and spinal where they increase arousal in the circadian sleep/wake cycle, reinforce learning and memory, and have roles in fluid balance, suppression of feeding, control of body temperature, control of cardiovascular system, and mediation of stress-triggered release of adrenocorticotropic hormone (ACTH) and b-endorphin from the pituitary gland.[10] It is not surprising then that antihistamines crossing the blood–brain barrier interfere with all of these processes.

Physiologically, the release of histamine during the day causes arousal, whereas its decreased production at night results in a passive reduction in the arousal response. When taken during the day, first-generation H₁-antihistamines, even in the manufacturers’ recommended doses, frequently cause daytime somnolence, sedation, drowsiness, fatigue, and impaired concentration and memory.[11,12] When taken at night, first-generation H₁-antihistamines increase the latency to the onset of rapid eye movement (REM) sleep and reduce the duration of REM sleep.[13–15] The residual effects of poor sleep, including impairment of attention, vigilance, working memory, and sensory motor performance, are still present in the next morning.[14,16] This is especially problematical with drugs with a long half-life [Table 1]. The detrimental central nervous system (CNS) effects of first-generation H₁-antihistamines on learning and examination performance in children and on impairment of the ability of adults to work, drive and fly aircraft have been reviewed in detail in a recent review.[17]

Table 1.

Half-lives of first-generation H₁-antihistamines

A major advance in antihistamine development occurred in the 1980s with the introduction of second-generation H₁-antihistamines,[18] which are minimally or nonsedating because of their limited penetration of the blood–brain barrier. In addition, these drugs are highly selective for the histamine H₁-receptor and have no anticholinergic effects. The latest EAACI/GA² LEN/EDF/WAO guidelines for the management of urticaria[19] recommend that the first-line treatment for urticaria should be second generation, nonsedating H₁-antihistamines. Further, it states “In patients with urticaria and no special indication, we recommend against the routine use of old sedating first-generation antihistamines (strong recommendation, high quality evidence).”

H₁-antihistamines in urticaria

Most types of urticaria, including chronic spontaneous urticaria and the majority of inducible urticarias, are mediated primarily by mast cell-derived histamine[20] which reaches very high concentrations due to the poor diffusibility of substances in the dermis.[21,22] They are characterized by short-lived wheals ranging from a few millimeters to several centimeters in diameter which are accompanied by severe itching which is usually worse in the evening or night-time.[23] Standard licensed doses of H₁-antihistamines are often ineffective in completely relieving symptoms in many patients for whom increasing the dosage up to four-fold is recommended.[19,24,25] Thus, it is clear that the attributes that dermatologists seek when choosing an H₁-antihistamine are: Good efficacy, a rapid onset of action, a long duration of action, and freedom from unwanted effects. Although some of these attributes may be predicted from preclinical and pharmacokinetic studies, it is only in the clinical environment that they may be definitively established.

Efficacy

Two factors determine the efficacy of an H₁-antihistamine: The affinity of the drug for H₁-receptors (absolute potency) and the concentration of the drug at the sites of the H₁-receptors. The affinity of an H₁-antihistamine for H₁-receptors is determined in vitro in preclinical studies. Comparing the three most recently developed drugs, desloratadine is the most potent antihistamine (Ki: 0.4 nM) followed by levocetirizine (Ki: 3 nM) and fexofenadine (Ki: 10 nM) (the lower the concentration, the higher the potency). The drug concentrations at its site of action could, theoretically, be calculated from its apparent volume of distribution (Vd) which are ~49, 0.4, and ~5.6 l/kg for desloratadine, levocetirizine, and fexofenadine, respectively.[26] However, Vd does not take into account other factors which influence local tissue concentrations in vivo, such as absorption, metabolism, and plasma binding. In the study of Gillard and colleagues,[27] concentrations of unbound drug in the plasma rather than Vd were used to calculate receptor occupancy, a theoretical indicator of effectiveness in vivo [Table 2]. The validity of these calculations of receptor occupancy is confirmed by the relative inhibition of wheal and flare responses by these drugs.[26,28–30]

Table 2.

Comparison of receptor occupancy for desloratadine, fexofenadine, and levocetirizine with inhibition of histamine-induced wheal and flare responses 4 and 24 h after drug administration

Speed of onset of action and duration of action

The speed of onset of action of a drug is often equated to the rate of its oral absorption and its duration of action by its plasma concentration. However, this is not strictly correct as seen from Figure 2. In this study, in children,[31,32] plasma concentrations of drug are near maximum by 30 min and yet it takes a further 1½ h for the drug to diffuse into the extravascular space to produce a maximal clinical effect. In adults, the maximal inhibition of the flare response is ~4 h for levocetirizine, fexofenadine, and desloratadine[28,30,33] but may be longer for drugs, such as loratadine and ebastine, which require metabolism to produce their active moiety.[28]

Figure 2.

Diagrammatic representation of the pharmacokinetics and pharmacodynamics of levocetirizine for a single oral dose of levocetirizine[31,32]

Figure 2 also shows that the duration of action of levocetirizine in inhibiting the histamine-induced flare response is also much longer than would be predicted from a knowledge of its plasma concentration.[31,32] This is presumably to “trapping” of the drug by its strong and long-lasting binding to histamine H₁-receptors.[8] Although less active in the wheal and flare test, desloratadine has a similarly long duration of action.[33] However, the duration of action of fexofenadine, calculated as the time for the wheal to remain inhibited by at least 70%, is less prolonged being 8.5 h for 120 mg fexofenadine compared with 19 h for cetirizine.[34] The primary reason for the shorter duration of action of fexofenadine is that it is actively secreted into the intestine and urine by P-glycoprotein.[35]

Elimination

The metabolism and elimination of H₁-antihistamines have been extensively reviewed elsewhere[26,36] and will be only briefly summarized here. Cetirizine and levocetirizine are not metabolized and are excreted primarily unchanged in the urine.[26] Desloratadine undergoes extensive metabolism in liver. Although this gives the potential for drug–drug interactions, no significant interactions have been reported[36] Fexofenadine, which is also minimally metabolized, is excreted primarily in the feces following its active secretion into the intestine under the influence of active drug transporting molecules.[36] This gives the potential for interactions with agents, such as grapefruit juice and St Johns Wort, which inhibit these transporters. Although plasma concentrations of fexofenadine may be increased by these agents, no significant resulting adverse reactions have been reported.[36]

Unwanted effects

Somnolence

A major reason for the reduced penetration of second-generation H₁-antihistamines into the brain is because their translocation across the blood–brain barrier is under the control of active transporter proteins, of which the ATP-dependent efflux pump, P-glycoprotein, is the best known.[37,38] It also became apparent that antihistamines differ in their substrate specificity for P-glycoprotein, fexofenadine being a particularly good substrate.[39] In the brain, the H₁-receptor occupancy of fexofenadine assessed using positron emission tomography (PET) scanning is negligible, <0.1%, and, in psychomotor tests, fexofenadine is not significantly different from placebo.[40] Furthermore, fexofenadine has been shown to be devoid of central nervous effects even at supraclinical doses, up to 360 mg.[41]

Although fexofenadine is devoid of CNS effects, many other second-generation H₁-antihistamines still penetrate the brain to a small extent where they have the potential to cause some degree of drowsiness or somnolence, particularly when used in higher doses. For example, PET scanning of the human brain has shown that a single oral doses of 10 mg and 20 mg cetirizine caused 12.5% and 25.2% occupancy of the H₁-receptors in prefrontal and cingulate cortices, respectively.[42] These results would explain the repeated clinical findings that the incidence of drowsiness or fatigue is greater with cetirizine than with placebo.[43–46] Recent publications have suggested that, at manufacturers’ recommended doses, levocetirizine is less sedative than cetirizine[47] and desloratadine causes negligible somnolence. [36,48] However, it should be pointed out that “mean results” do not reveal everything as some patients may show considerable somnolence, whereas others are unaffected.

Cardiotoxicity

The propensity of astemizole and terfenadine, to block the I_Kr current, to prolong the QT interval, and to potentially cause serious polymorphic ventricular arrhythmias such as torsades de pointes is well documented.[6,49] These two drugs are no longer approved by regulatory agencies in most countries. In addition, some first-generation H₁-antihistamines, such as promethazine,[50] brompheniramine,[51] and diphenhydramine,[52] may also be associated with a prolonged QTc and cardiac arrhythmias when taken in large doses or overdoses. No clinically significant cardiac effects have been reported for the second-generation H₁-antihistamines: Loratadine, fexofenadine, mizolastine, ebastine, azelastine, cetirizine, desloratadine, and levocetirizine.[53–56]

Conclusions

In conclusion, the use of first-generation H₁-antihistamines should be discouraged in clinical practice today for two main reasons. First, they are less effective than second-generation H₁-antihistamines.[11,57,58] Second, they have unwanted side effects and the potential for causing severe toxic reactions which are not shared by second-generation H₁-antihistamines. The only exception to this is where severe pruritus is of particular concern where drugs such as hydroxyzine may be of use.[59] Indeed, Simons in her review of antihistamines in children[60] writes that in children with urticaria or atopic dermatitis whose pruritus is very severe, the sedation produced by an old H₁-antihistamine, such as hydroxyzine, is a benefit rather than a risk.

With regard to second-generation H₁-antihistamines, there are many efficacious and safe drugs on the market for the treatment of allergic disease. Of the three drugs highlighted in this review, levocetirizine and fexofenadine are the most potent in humans in vivo. However, levocetirizine may cause somnolence in susceptible individuals, whereas fexofenadine has a relatively short duration of action and may be required to be given twice daily for all round daily protection. Although desloratadine is less potent, it has the advantages of rarely causing somnolence and having a long duration of action.