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Table of Contents 
SYMPOSIUM
Year : 2013  |  Volume : 58  |  Issue : 3  |  Page : 219-224
Pharmacology of antihistamines


1 Allergie Centrum Charité/ECARF, Charité Universitätsmedizin Berlin, Germany
2 Highlands Medical Centre, Fareham, Hampshire, Germany

Date of Web Publication20-Apr-2013

Correspondence Address:
Martin K Church
Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, Charitéplatz 1, D 10117 Berlin
Germany
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Source of Support: Martin Church has been a speaker or consultant for Almirall, FAES Pharma, Menarini, MSD, UCB Pharma, Sanofi-Aventis, and Uriach. Diana Church has no conflict of interest., Conflict of Interest: None


DOI: 10.4103/0019-5154.110832

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   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 H 1 -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 H 1 -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.


Keywords: Cetirizine, desloratadine, fexofenadine, H 1 -antihistamines, hydroxyzine, levocetirizine, loratadine


How to cite this article:
Church MK, Church DS. Pharmacology of antihistamines . Indian J Dermatol 2013;58:219-24

How to cite this URL:
Church MK, Church DS. Pharmacology of antihistamines . Indian J Dermatol [serial online] 2013 [cited 2018 Nov 14];58:219-24. Available from: http://www.e-ijd.org/text.asp?2013/58/3/219/110832



   Introduction Top


To understand H 1 -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 H 1 -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 H 1 -receptor

The histamine H 1 -receptor is a member of the superfamily of G-protein-coupled receptors (GPCRs) [Figure 1]a. 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 H 1 -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 1]b. H 1 -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 1]c. Thus, H 1 -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 "H 1 -antihistamines" rather than "histamine antagonists."

The development of H 1 -antihistamines
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

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Bearing in mind that first-generation H 1 -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 H 1 -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 H 1 -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 H 1 -antihistamines increase the latency to the onset of rapid eye movement (REM) sleep and reduce the duration of REM sleep. [13],[14],[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 H 1 -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


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A major advance in antihistamine development occurred in the 1980s with the introduction of second-generation H 1 -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 H 1 -receptor and have no anticholinergic effects. The latest EAACI/GA 2 LEN/EDF/WAO guidelines for the management of urticaria [19] recommend that the first-line treatment for urticaria should be second generation, nonsedating H 1 -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)."

H 1 -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 H 1 -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 H 1 -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 H 1 -antihistamine: The affinity of the drug for H 1 -receptors (absolute potency) and the concentration of the drug at the sites of the H 1 -receptors. The affinity of an H 1 -antihistamine for H 1 -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],[29],[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


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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]

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[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 H 1 -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 H 1 -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 H 1 -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 H 1 -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 H 1 -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 H 1 -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],[44],[45],[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 IKr 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 H 1 -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 H 1 -antihistamines: Loratadine, fexofenadine, mizolastine, ebastine, azelastine, cetirizine, desloratadine, and levocetirizine. [53],[54],[55],[56]


   Conclusions Top


In conclusion, the use of first-generation H 1 -antihistamines should be discouraged in clinical practice today for two main reasons. First, they are less effective than second-generation H 1 -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 H 1 -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 H 1 -antihistamine, such as hydroxyzine, is a benefit rather than a risk.

With regard to second-generation H 1 -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.

 
   References Top

1.Bovet D. Introduction to antihistamine agents and antergan derivative. Ann N Y Acad Sci 1950;50:1089-126.  Back to cited text no. 1
    
2.Staub AM, Bovet D. Action de la thymoxyethyldiethylamine (929F) et des ethers phenoliques sur le choc anaphylactique. C R Soc Biol 1937;125:818-21.  Back to cited text no. 2
    
3.Halpern BN. Les antihistaminiques de synthese. Essais de chemotherapie des etats allergiques. Arch Int Pharmacodyn Ther 1942;681:339-408.  Back to cited text no. 3
    
4.Loew ER, Macmillan R, Kaiser ME. The anti-histamine properties of benadryl, beta-di-methylaminoethyl benzhydryl ether hydrochloride. J Pharmacol Exp Ther 1946;86:229-38.  Back to cited text no. 4
    
5.Emanuel MB. Histamine and the antiallergic antihistamines: A history of their discoveries. Clin Exp Allergy 1999;29:1-11.  Back to cited text no. 5
    
6.Leurs R, Church MK, Taglialatela M. H1-antihistamines: Inverse agonism, anti-inflammatory actions and cardiac effects. Clin Exp Allergy 2002;32:489-98.  Back to cited text no. 6
    
7.Wieland K, Laak AM, Smit MJ, Kühne R, Timmerman H, Leurs R. Mutational analysis of the antagonist-binding site of the histamine H (1) receptor. J Biol Chem 1999;274:29994-30000.  Back to cited text no. 7
    
8.Gillard M, Van Der Perren C, Moguilevsky N, Massingham R, Chatelain P. Binding characteristics of cetirizine and levocetirizine to human H (1) histamine receptors: Contribution of Lys (191) and Thr (194). Mol Pharmacol 2002;61:391-9.  Back to cited text no. 8
    
9.Haas H, Panula P. The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci 2003;4:121-30.  Back to cited text no. 9
    
10.Brown RE, Stevens DR, Haas HL. The physiology of brain histamine. Prog Neurobiol 2001;63:637-72.  Back to cited text no. 10
    
11.Simons FE. Advances in H1-antihistamines. N Engl J Med 2004;351:2203-17.  Back to cited text no. 11
    
12.Juniper EF, Ståhl E, Doty RL, Simons FE, Allen DB, Howarth PH. Clinical outcomes and adverse effect monitoring in allergic rhinitis. J Allergy Clin Immunol 2005;115:S390-413.  Back to cited text no. 12
    
13.Adam K, Oswald I. The hypnotic effects of an antihistamine: Promethazine. Br J Clin Pharmacol 1986;22:715-7.  Back to cited text no. 13
    
14.Boyle J, Eriksson M, Stanley N, Fujita T, Kumagi Y. Allergy medication in Japanese volunteers: Treatment effect of single doses on nocturnal sleep architecture and next day residual effects. Curr Med Res Opin 2006;22:1343-51.  Back to cited text no. 14
    
15.Rojas-Zamorano JA, Esqueda-Leon E, Jimenez-Anguiano A, Cintra-McGlone L, Mendoza Melendez MA, Velazquez Moctezuma J. The H1 histamine receptor blocker, chlorpheniramine, completely prevents the increase in REM sleep induced by immobilization stress in rats. Pharmacol Biochem Behav 2009;91:291-4.  Back to cited text no. 15
    
16.Kay GG, Berman B, Mockoviak SH, Morris CE, Reeves D, Starbuck V, et al. Initial and steady-state effects of diphenhydramine and loratadine on sedation, cognition, mood, and psychomotor performance. Arch Intern Med 1997;157:2350-6.  Back to cited text no. 16
    
17.Church MK, Maurer M, Simons FE, Bindslev-Jensen C, van Cauwenberge P, Bousquet J, et al. Risk of first-generation H (1)-antihistamines: A GA (2) LEN position paper. Allergy 2010;65:459-66.  Back to cited text no. 17
    
18.Holgate ST, Canonica GW, Simons FE, Taglialatela M, Tharp M, Timmerman H, et al. Consensus Group on New-Generation Antihistamines (CONGA): Present status and recommendations. Clin Exp Allergy 2003;33:1305-24.  Back to cited text no. 18
    
19.Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Giménez-Arnau AM, et al. EAACI/GA (2) LEN/EDF/WAO guideline: Management of urticaria. Allergy 2009;64:1427-43.  Back to cited text no. 19
    
20.Nuutinen P, Harvima IT, Ackermann L. Histamine, but not leukotriene C4, is an essential mediator in cold urticaria wheals. Acta Derm Venereol 2007;87:9-13.  Back to cited text no. 20
    
21.Petersen LJ, Church MK, Skov PS. Histamine is released in the wheal but not the flare following challenge of human skin in vivo: A microdialysis study. Clin Exp Allergy 1997;27:284-95.  Back to cited text no. 21
    
22.Stenken JA, Church MK, Gill CA, Clough GF. How minimally invasive is microdialysis sampling? A cautionary note for cytokine collection in human skin and other clinical studies. AAPS J 2010;12:73-8.  Back to cited text no. 22
    
23.Maurer M, Weller K, Bindslev-Jensen C, Giménez-Arnau A, Bousquet PJ, Bousquet J, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy 2011;66:317-30.  Back to cited text no. 23
    
24.Wedi B, Kapp A. Chronic urticaria: Assessment of current treatment. Expert Rev Clin Immunol 2005;1:459-73.  Back to cited text no. 24
    
25.Powell RJ, Du Toit GL, Siddique N, Leech SC, Dixon TA, Clark AT, et al. BSACI guidelines for the management of chronic urticaria and angio-oedema. Clin Exp Allergy 2007;37:631-50.  Back to cited text no. 25
    
26.Molimard M, Diquet B, Benedetti MS. Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humans. Fundam Clin Pharmacol 2004;18:399-411.  Back to cited text no. 26
    
27.Gillard M, Benedetti MS, Chatelain P, Baltes E. Histamine H1 receptor occupancy and pharmacodynamics of second generation H1-antihistamines. Inflamm Res 2005;54:367-9.  Back to cited text no. 27
    
28.Grant JA, Riethuisen JM, Moulaert B, DeVos C. A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo: Suppression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects. Ann Allergy Asthma Immunol 2002;88:190-7.  Back to cited text no. 28
    
29.Denham KJ, Boutsiouki P, Clough GF, Church MK. Comparison of the effects of desloratadine and levocetirizine on histamine-induced wheal, flare and itch in human skin. Inflamm Res 2003;52:424-7.  Back to cited text no. 29
    
30.Purohit A, Melac M, Pauli G, Frossard N. Comparative activity of cetirizine and desloratadine on histamine-induced wheal-and-flare responses during 24 hours. Ann Allergy Asthma Immunol 2004;92:635-40.  Back to cited text no. 30
    
31.Simons FE, Simons KJ. Levocetirizine: Pharmacokinetics and pharmacodynamics in children age 6 to 11 years. J Allergy Clin Immunol 2005;116:355-61.  Back to cited text no. 31
    
32.Simons KJ, Benedetti MS, Simons FE, Gillard M, Baltes E. Relevance of H1-receptor occupancy to H1-antihistamine dosing in children. J Allergy Clin Immunol 2007;119:1551-4.  Back to cited text no. 32
    
33.Purohit A, Melac M, Pauli G, Frossard N. Twenty-four-hour activity and consistency of activity of levocetirizine and desloratadine in the skin. Br J Clin Pharmacol 2003;56:388-94.  Back to cited text no. 33
    
34.Purohit A, Duvernelle C, Melac M, Pauli G, Frossard N. Twenty-four hours of activity of cetirizine and fexofenadine in the skin. Ann Allergy Asthma Immunol 2001;86:387-92.  Back to cited text no. 34
    
35.Miura M, Uno T. Clinical pharmacokinetics of fexofenadine enantiomers. Expert Opin Drug Metab Toxicol 2010;6:69-74.  Back to cited text no. 35
    
36.Devillier P, Roche N, Faisy C. Clinical pharmacokinetics and pharmacodynamics of desloratadine, fexofenadine and levocetirizine: A comparative review. Clin Pharmacokinet 2008;47:217-30.  Back to cited text no. 36
    
37.Schinkel AH. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev 1999;36:179-94.  Back to cited text no. 37
    
38.Chen C, Hanson E, Watson JW, Lee JS. P-glycoprotein limits the brain penetration of nonsedating but not sedating H1-antagonists. Drug Metab Dispos 2003;31:312-8.  Back to cited text no. 38
    
39.Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB. OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos 1999;27:866-71.  Back to cited text no. 39
    
40.Tashiro M, Sakurada Y, Iwabuchi K, Mochizuki H, Kato M, Aoki M, et al. Central effects of fexofenadine and cetirizine: Measurement of psychomotor performance, subjective sleepiness, and brain histamine H1-receptor occupancy using 11C-doxepin positron emission tomography. J Clin Pharmacol 2004;44:890-900.  Back to cited text no. 40
    
41.Hindmarch I, Shamsi Z, Kimber S. An evaluation of the effects of high-dose fexofenadine on the central nervous system: A double-blind, placebo-controlled study in healthy volunteers. Clin Exp Allergy 2002;32:133-9.  Back to cited text no. 41
    
42.Tashiro M, Kato M, Miyake M, Watanuki S, Funaki Y, Ishikawa Y, et al. Dose dependency of brain histamine H (1) receptor occupancy following oral administration of cetirizine hydrochloride measured using PET with [11C] doxepin. Hum Psychopharmacol 2009;24:540-8.  Back to cited text no. 42
    
43.Meltzer EO, Weiler JM, Widlitz MD. Comparative outdoor study of the efficacy, onset and duration of action, and safety of cetirizine, loratadine, and placebo for seasonal allergic rhinitis. J Allergy Clin Immunol 1996;97:617-26.  Back to cited text no. 43
    
44.Howarth PH, Stern MA, Roi L, Reynolds R, Bousquet J. Double-blind, placebo-controlled study comparing the efficacy and safety of fexofenadine hydrochloride (120 and 180 mg once daily) and cetirizine in seasonal allergic rhinitis. J Allergy Clin Immunol 1999;104:927-33.  Back to cited text no. 44
    
45.Salmun LM, Gates D, Scharf M, Greiding L, Ramon F, Heithoff K. Loratadine versus cetirizine: Assessment of somnolence and motivation during the workday. Clin Ther 2000;22:573-82.  Back to cited text no. 45
    
46.Mann RD, Pearce GL, Dunn N, Shakir S. Sedation with "non-sedating" antihistamines: Four prescription-event monitoring studies in general practice. BMJ 2000;320:1184-6.  Back to cited text no. 46
    
47.De Vos C, Mitchev K, Pinelli ME, Derde MP, Boev R. Non-interventional study comparing treatment satisfaction in patients treated with antihistamines. Clin Drug Investig 2008;28:221-30.  Back to cited text no. 47
    
48.Day JH, Briscoe MP, Rafeiro E, Ratz JD. Comparative clinical efficacy, onset and duration of action of levocetirizine and desloratadine for symptoms of seasonal allergic rhinitis in subjects evaluated in the Environmental Exposure Unit (EEU). Int J Clin Pract 2004;58:109-18.  Back to cited text no. 48
    
49.Woosley RL. Cardiac actions of antihistamines. Annu Rev Pharmacol Toxicol 1996;36:233-52.  Back to cited text no. 49
    
50.Jo SH, Hong HK, Chong SH, Lee HS, Choe H. H (1) antihistamine drug promethazine directly blocks hERG K(+) channel. Pharmacol Res 2009;60:429-37.  Back to cited text no. 50
    
51.Park SJ, Kim KS, Kim EJ. Blockade of HERG K+channel by an antihistamine drug brompheniramine requires the channel binding within the S6 residue Y652 and F656. J Appl Toxicol 2008;28:104-11.  Back to cited text no. 51
    
52.Zareba W, Moss AJ, Rosero SZ, Hajj-Ali R, Konecki J, Andrews M. Electrocardiographic findings in patients with diphenhydramine overdose. Am J Cardiol 1997;80:1168-73.  Back to cited text no. 52
    
53.Ten Eick AP, Blumer JL, Reed MD. Safety of antihistamines in children. Drug Saf 2001;24:119-47.  Back to cited text no. 53
    
54.DuBuske LM. Second-generation antihistamines: The risk of ventricular arrhythmias. Clin Ther 1999;21:281-95.  Back to cited text no. 54
    
55.Simons FE, Prenner BM, Finn A Jr, Desloratadine Study Group. Efficacy and safety of desloratadine in the treatment of perennial allergic rhinitis. J Allergy Clin Immunol 2003;111:617-22.  Back to cited text no. 55
    
56.Hulhoven R, Rosillon D, Letiexhe M, Meeus MA, Daoust A, Stockis A. Levocetirizine does not prolong the QT/QTc interval in healthy subjects: Results from a thorough QT study. Eur J Clin Pharmacol 2007;63:1011-7.  Back to cited text no. 56
    
57.Simons FE. Comparative pharmacology of H1 antihistamines: Clinical relevance. Am J Med 2002;113:38S-46.  Back to cited text no. 57
    
58.Simons FE, Silver NA, Gu X, Simons KJ. Clinical pharmacology of H1-antihistamines in the skin. J Allergy Clin Immunol 2002;110:777-83.  Back to cited text no. 58
    
59.Shohrati M, Davoudi SM, Keshavarz S, Sadr B, Tajik A. Cetirizine, doxepine, and hydroxyzine in the treatment of pruritus due to sulfur mustard: A randomized clinical trial. Cutan Ocul Toxicol 2007;26:249-55.  Back to cited text no. 59
    
60.Simons FE. H1-antihistamines in children. Clin Allergy Immunol 2002;17:437-64.  Back to cited text no. 60
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]

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