H1 Antihistamines: Current Status and Future Directions

In this review, we compare and contrast the clinical pharmacology, efficacy, and safety of first-generation H1 antihistamines and second-generation H1 antihistamines. First-generation H1 antihistamines cross the blood-brain barrier, and in usual doses, they potentially cause sedation and impair cognitive function and psychomotor performance. These medications, some of which have been in use for more than 6 decades, have never been optimally investigated. Second-generation H1 antihistamines such as cetirizine, desloratadine, fexofenadine, levocetirizine, and loratadine cross the blood-brain barrier to a significantly smaller extent than their predecessors. The clinical pharmacology, efficacy, and safety of these medications have been extensively studied. They are therefore the H1 antihistamines of choice in the treatment of allergic rhinitis, allergic conjunctivitis, and urticaria. In the future, clinically advantageous H1 antihistamines developed with the aid of molecular techniques might be available.

H istamine, a natural body constituent, is synthesized from L-histidine exclusively by histidine decarboxylase, an enzyme expressed in central nervous system (CNS) neurons, gastric mucosa parietal cells, mast cells, basophils, and other cells throughout the body. Histamine plays a major role in human health, exerting its diverse effects through 4 or more types of receptors (Table 1). Through the H 1 receptor, histamine is involved in cell proliferation and differentiation, hematopoiesis, embryonic development, regeneration, and wound healing. It is a neurotransmitter, has anticonvulsant activity, and contributes to regulation of the sleep-waking cycle, energy and endocrine homeostasis, cognition and memory. 1,2 Through all 4 known types of histamine receptors, histamine also plays an important role in immune modulation and in acute and chronic allergic inflammation. Through the H 1 receptor, it increases antigen-presenting cell capacity, increases release of histamine and other mediators from mast cells and basophils, up-regulates cellular adhesion molecule expression and chemotaxis of eosinophils and neutrophils, up-regulates Th1 priming and Th1 cell proliferation and interferon-F production, and down-regulates humoral immunity. Through the H 2 receptor, it suppresses inflammatory and effector functions. Through the presynaptic H 3 receptor on histaminergic and nonhistaminergic neurons in the central and peripheral nervous systems, it is probably involved in control of neurogenic inflammation through mast cell feedback loops. Through the H 4 receptor, it facilitates some proinflammatory activities (Table 1). 1 Targeted disruption of the H 1 receptor gene in mice results in impairment of neurological functions such as memory, learning, and locomotion, and in aggressive behavior. In addition, mice that are H 1 receptorYdeficient have immunologic abnormalities, including impaired antigenspecific B-cell and T-cell responses. 1Y3 All 4 types of histamine receptors are heptahelical transmembrane molecules that transduce extracellular signals, by way of G-proteins, to intracellular second messenger systems. Histamine receptors have constitutive activity, which is defined as the ability to trigger downstream events, even in the absence of ligand binding. The active and inactive states of these receptors exist in equilibrium; at rest, the inactive state isomerizes with the active state and vice versa. 2,3 H 1 Antihistamines H 1 antihistamines act as inverse agonists that combine with and stabilize the inactive conformation of the H 1 receptor, shifting the equilibrium toward the inactive state. H 1receptor polymorphisms have been described, although it is not yet clear how they influence the clinical response to H 1 antihistamines. Human H 1 receptors have approximately 45% homology with muscarinic receptors. 2,3 H 1 antihistamines down-regulate allergic inflammation through the H 1 receptor, either directly or indirectly through nuclear factor-JB, an ubiquitous transcription factor, through which they down-regulate antigen presentation, expression of proinflammatory cytokines and cell adhesion molecules, and chemotaxis. In addition, through their effects on calcium ion channel activity, H 1 antihistamines decrease mediator release; however, this effect is only seen at high H 1 -antihistamine concentrations. 2 Traditionally, H 1 antihistamines have been classified into 6 chemical groups: alkylamines, ethanolamines, ethylenediamines, phenothiazines, piperazines, and piperidines. Currently, the most commonly used classification system is a functional one, in which H 1 antihistamines are classified as either first-generation medications that readily cross the bloodbrain barrier and potentially sedate and impair cognitive and psychomotor function, or second-generation drugs that cross the blood-brain barrier to a minimal extent and are relatively nonsedating and nonimpairing 2Y4 (Table 2). H 1 antihistamines, formerly known as H 1 receptor antagonists or H 1 receptor blockers, are among the most commonly used medications in the world not only for prevention and treatment of symptoms in allergic rhinitis, allergic conjunctivitis, and urticaria, in which there is good evidence for their efficacy, but also for a variety of other allergic and nonallergic diseases, in which there is no satisfactory evidence for their efficacy. More than 40 H 1 antihistamines are available worldwide. Health care professionals Results are expressed as mean T SD, unless otherwise indicated. *Clinically relevant drug-drug interactions are unlikely with most of the second-generation H 1 antihistamines. **Onset/duration of action is based on wheal and flare studies. ‡ Five or 6 decades ago when many of the first-generation H 1 antihistamines were introduced, pharmacokinetic and pharmacodynamic studies were not required by regulatory agencies. They have subsequently been performed for some of these drugs. Empirical dosage regimens persist; for example, the manufacturers' recommended diphenhydramine dose for allergic rhinitis is 25 to 50 mg every 4 to 6 hours, and the diphenhydramine dose for insomnia is 25 to 50 mg at bedtime. The use of sustained-action formulations persists, despite the long terminal elimination half-life values identified for medications such as chlorpheniramine. § Intranasal and ophthalmic H 1 antihistamines: t max , t1/2, and drug-drug interactions were determined after oral administration. || Intranasal and ophthalmic H 1 antihistamine formulations: onset and duration of action is based on usual adult dose of 1 to 2 sprays in each nostril or 1 drop in each eye. n/a indicates information not available or incomplete. Adapted from Simons. 2 Azatadine, cyproheptadine, diphenylpyraline, ketotifen ‡ Astemizole,** bilastine,** desloratadine,* ebastine,** fexofenadine,* levocabastine, ‡ loratadine,* mizolastine,** olopatadine, ‡ rupatadine,** terfenadine*,** Ethanolamines Carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, doxylamine, phenyltoloxamine** V Ethylenediamines Antazoline, pyrilamine, tripelennamine V Phenothiazines Methdilazine, promethazine V Other Doxepin § Azelastine, ‡ emedastine, ‡ epinastine ‡ *Acrivastine is related tripolidine. Cetirizine is a metabolite of hydroxyzine, levocetirizine is an enantiomer of cetirizine, desloratadine is a metabolite of loratadine, and fexofenadine is a metabolite of terfenadine. **In the United States, these H 1 antihistamines are not yet approved, have never been approved, or have had approval withdrawn. ‡ The H 1 antihistamines azelastine, emedastine, epinastine, ketotifen, levocabastine, and olopatadine are available in ophthalmic formulations; and azelastine, dimethindene, levocabastine, and olopatadine are available in intranasal formulations. In some countries, azelastine, dimethindene, ketotifen, and olopatadine are also available in oral formulations. § Doxepin has H 1 and H 2 antihistamine activities and is also classified as a tricyclic antidepressant. Adapted from Simons. 2 and consumers generally assume that all H 1 antihistamines approved for use are proven to be efficacious and safe. This is an incorrect assumption with regard to the first-generation medications in this class, most of which were introduced decades before clinical pharmacology studies and randomized controlled trials of medication efficacy and safety were required by regulatory agencies. In contrast, the secondgeneration H 1 antihistamines, particularly cetirizine, desloratadine, fexofenadine, levocetirizine, and loratadine, have been systematically and thoroughly investigated in clinical pharmacology studies and in randomized placebo-controlled trials in allergic rhinoconjunctivitis and chronic urticaria. 2Y4 In this review, we compare the clinical pharmacology, efficacy, and safety of the first-generation H 1 antihistamines with those of the second-generation H 1 antihistamines.

CLINICAL PHARMACOLOGY OF H 1 ANTIHISTAMINES
For most of the first-generation H 1 antihistamines, pharmacokinetics (absorption, distribution, metabolism, and elimination) have never been optimally investigated, and pharmacodynamic studies in which drug concentrations and activity are correlated have not been performed. Clinically relevant information about the time at which maximum plasma concentrations are achieved, the terminal elimination half-life values, and the onset and duration of action is therefore available for only a few of these medications (Table 3A). Moreover, there are few prospective clinical pharmacology studies of these older H 1 antihistamines in infants, children, the elderly, or people with impaired hepatic or renal function, and there are few studies of their interactions with other drugs, foods, or herbal products. 2Y5

Pharmacokinetics of Second-Generation H 1 Antihistamines
For most of the second-generation H 1 antihistamines, pharmacokinetics have been well studied (Table 3A). After oral administration, peak plasma concentrations of these medications are reached in 1 to 2 hours. Terminal elimination half-life values range from about 6 hours for cetirizine, levocetirizine, and loratadine to 27 hours for desloratadine. Some of these medications such as loratadine and desloratadine are metabolized, but others are not; for example, cetirizine and levocetirizine are eliminated mostly unchanged in the urine, and fexofenadine is eliminated mostly unchanged in the feces. The pharmacokinetics of these newer H 1 antihistamines have been studied in healthy adults, and also in infants, children, the elderly, and individuals with impaired hepatic or renal function. In drug-drug interaction studies, few clinically relevant issues have been identified, however, additional interaction studies with foods and with herbal products are needed. 2Y8

Pharmacodynamics of Second-Generation H 1 Antihistamines
Pharmacodynamic studies involving suppression of the response to nasal or conjunctival allergen challenge tests are helpful in determining the onset and intensity of action of H 1 antihistamines. 9 More commonly, however, the pharmacodynamics of H 1 antihistamines are assessed by measuring suppression of the histamine-induced wheal and flare (erythema). In randomized placebo-controlled studies using this unique model, statistically significant and clinically relevant differences among the second-generation H 1 antihistamines have been identified with regard to onset and intensity of action, time to peak effect, and duration of effect. 2Y8 Wheal and flare suppression correlates better with tissue H 1 -antihistamine concentrations than with plasma H 1 -antihistamine concentrations, and correlates best with H 1 receptor occupancy by free unbound drug, where such data are available. 2,3,5Y8,10Y12 The onset of action of orally administered secondgeneration H 1 antihistamines occurs from 1 hour after oral administration (for cetirizine and levocetirizine) to 2 hours (for desloratadine, fexofenadine, and loratadine; Table 3A). Most second-generation H 1 antihistamines have a duration of action of at least 24 hours, facilitating once-daily dosing. Tolerance to their effects during regular daily dosing does not occur. Residual effects after discontinuation of regular daily dosing last from 1 to 4 days. 2,3,5Y8,10,11

Pharmacokinetics and Pharmacodynamics of Intranasal and Ophthalmic H 1 -Antihistamine Formulations
Although some systemic absorption occurs within minutes of topical and ophthalmic formulations of H 1 antihistamines such as azelastine, emedastine, epinastine, levocabastine, and olopatadine, and is potentially associated with transient suppression of skin test reactivity, the amount of suppression is seldom clinically relevant. The elimination half-life of these medications ranges from 7 to 40 hours (Table 3B); however, they are all administered at 6-to 12-hour intervals because of washout from the nasal mucosa or conjunctivae. No dose adjustments are required in special populations. 3,9,13 EFFICACY OF H 1 ANTIHISTAMINES IN ALLERGIC DISEASES H 1 antihistamines prevent and relieve allergic inflammation and associated symptoms in seasonal/intermittent (perennial/persistent) allergic rhinitis, allergic conjunctivitis, and urticaria (Table 4A). Symptom relief may be incomplete because leukotrienes and other agents released from mast cells and basophils also play a role in allergic inflammation. H 1 antihistamines are best taken on a regular basis rather than on an as-needed basis. Few of the randomized placebocontrolled clinical trials of first-generation H 1 antihistamines that have been performed in the past 6 decades meet current standards. In contrast, the use of second-generation H 1 antihistamines for relief of symptoms in seasonal/intermittent and perennial/persistent allergic rhinoconjunctivitis and chronic urticaria is supported by hundreds of appropriately randomized, double-masked, placebo-controlled clinical trials lasting weeks or months, in which inclusion criteria and exclusion criteria are clearly stated, an adequate number of participants is enrolled, and attrition and adherence are appropriately documented. Second-generation H 1 antihistamines are therefore the H 1 antihistamines of choice in the treatment of allergic rhinitis, allergic conjunctivitis, and chronic urticaria. 2Y5,13Y16

Allergic Rhinoconjunctivitis
In allergic rhinoconjunctivitis, second-generation H 1 antihistamines improve quality of life by preventing and relieving the sneezing, nasal and conjunctival itching, rhinorrhea, tearing, and conjunctival erythema of the early response to allergen. A small beneficial effect is also reported for the nasal congestion that characterizes the late allergic response. Cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, and other second-generation H 1 antihistamines have significantly greater efficacy than placebo, as documented in well-designed, randomized, placebo-controlled trials (Table 4A). In the few published studies in which their efficacy relative to each other or to first-generation H 1 antihistamines has been investigated, no overall superior efficacy of one H 1 antihistamine over another has been consistently documented. Additional comparative, randomized, controlled trials of second-generation H 1 antihistamines are needed. 2Y5,7,8,13Y22 Intranasal or ophthalmic H 1 -antihistamine formulations have a more rapid onset of action than oral H 1 -antihistamine formulations; for example, 15 minutes for intranasal azelastine versus 150 minutes for oral desloratadine; however, as noted previously, these formulations require administration several times daily. 9,13,22 In many individuals with allergic rhinoconjunctivitis in whom eye symptoms predominate, H 1 antihistamines applied to the conjunctivae are the medications of choice not only for their antihistaminic effects, but also for their mast cellY stabilizing effects, and their rapid onset of action (range, 3Y15 minutes). H 1 antihistamines, whether administered orally or applied directly to the conjunctivae, have a more favorable therapeutic index than any of the other classes of medications used for allergic conjunctivitis (Table 4A). 3,13,22 Selection of an H 1 antihistamine for an individual with allergic rhinoconjunctivitis should be based on his/her preference for a particular H 1 -antihistamine formulation, route of administration, or dose regimen, and on considerations of potential benefits versus potential adverse effects.
Second-generation H 1 antihistamines have similar efficacy to intranasal cromolyn, intranasal nedocromil, and leukotriene modifiers in seasonal allergic rhinitis. The combination of desloratadine or levocetirizine with montelukast might be more efficacious than monotherapy with any one of these agents; however, a combined loratadine/montelukast formulation has failed to gain US Food and Drug Administration (FDA) approval. To provide increased relief of nasal congestion, H 1 antihistamines are sometimes marketed in fixed-dose combinations with pseudoephedrine or other decongestants. H 1 antihistamines are less efficacious than intranasal glucocorticoids, especially for relief of nasal congestion. 2,3,14,16 Urticaria H 1 antihistamines are efficacious in acute urticaria, defined as hives lasting less than 6 weeks, and in chronic urticaria, defined as hives lasting 6 weeks or more, including physical urticarias such as cholinergic, cold, aquagenic, and delayed pressure-induced urticaria. They decrease itching, reduce the number, size, and duration of wheals and flares (erythema), and improve quality of life significantly. 2,3,5,23Y29 They are not efficacious in urticarial vasculitis.
In acute urticaria, both first-and second-generation H 1 antihistamines are widely used, however, there are surprisingly few randomized controlled trials in support of this practice. In 2 different large, randomized, double-masked, placebocontrolled studies in young atopic children in which efficacy in preventing and treating acute urticaria was a planned secondary outcome, cetirizine and levocetirizine had statistically significant and clinically relevant beneficial effects. 23Y26 The first-generation H 1 antihistamines remain in widespread use for chronic urticaria, despite lack of randomized placebo-controlled efficacy trials that meet current standards, and despite concerns about their potential adverse effects. In contrast, the second-generation H 1 antihistamines cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, and others have been well studied in chronic urticaria and are therefore the cornerstone of treatment in this disease ( Table 4A ). 2,3,5,7,8,27Y29 In chronic urticaria that is unresponsive to a secondgeneration H 1 antihistamine in a standard dose, a variety of therapeutic strategies are recommended. 26 High (off-label) doses of second-generation H 1 antihistamines have been prospectively tested in a few randomized, double-masked, placebo-controlled trials and may offer some advantage. Use of 2 different second-generation H 1 antihistamines on the same day or use of a nonsedating H 1 antihistamine in the morning and a sedating H 1 antihistamine at night is commonly recommended based on tradition and clinical experience. Prospective, randomized, controlled trials of these treatment regimens are long overdue.
Some but not all individuals with severe chronic urticaria that is unresponsive to H 1 antihistamines will respond to montelukast or to an H 2 antihistamine such as cimetidine. Individuals with intractable pruritus might require a course of treatment with an immunomodulator such as an oral corticosteroid, cyclosporin, hydroxychloroquine, omalizumab, dapsone, colchicine, sulfasalazine, mycophenolate, or oral tacrolimus.
Montelukast has been studied in large, randomized, placebo-controlled trials in chronic urticaria and cyclosporine, hydroxychloroquine, and omalizumab have been studied in small, randomized, placebo-controlled trials. None of the other pharmacological interventions used in chronic urticaria refractory to antihistamine treatment have been studied in randomized, placebo-controlled trials. With the exception of antihistamines and montelukast, immunomodulators used in chronic urticaria have potentially severe adverse effects, and individuals taking them need to be monitored on a regular basis. 13

Atopic Dermatitis and Other Skin Disorders
The evidence that H 1 antihistamines relieve itch in atopic dermatitis is limited to a study of fexofenadine in which itching was the only outcome measure and a study of cetirizine in which off-label doses as high as 40 mg were administered. In atopic dermatitis, histamine may act as a pruritogen not only through H 1 receptors, but also through H 3 and H 4 receptors; in addition, cytokines such as interleukin-31 and other agents may be important pruritogens (Table 4B). 30Y32 The use of H 1 antihistamines to relieve symptoms in individuals with mastocytosis or to prevent and relieve itchy local allergic reactions to mosquito bites is supported by small, randomized, controlled trials. 3 Asthma Pretreatment with an H 1 antihistamine provides significant protection against bronchospasm induced by histamine, adenosine-5 monophosphate, or allergen, but less protection against bronchospasm induced by exercise or other stimuli. H 1 antihistamines decrease symptoms significantly in many individuals with concurrent seasonal allergic rhinitis and mild asthma; however, they have a greater effect on the rhinitis symptoms than on the asthma symptoms. In an 18-month-long study in very young children with atopic dermatitis and housedust mite or grass sensitization who were at risk for developing asthma, cetirizine treatment delayed asthma onset, but     in a subsequent study in highly atopic young children, this observation was not confirmed with levocetirizine (Table 4B). 2,3,5,33,34 Anaphylaxis A recent Cochrane collaboration review of 2070 studies of H 1 antihistamines in anaphylaxis did not reveal any study that provided evidence for the use of H 1 antihistamines in this disease. Individuals who require first-aid treatment of anaphylaxis occurring in a community setting should not depend on an oral H 1 antihistamine because onset of action takes 1 to 2 hours, and although these medications decrease itch and hives, they do not relieve upper or lower respiratory tract obstruction or circulatory collapse and do not prevent fatality (Table 4B). 35

Nonallergic Angioedema
Nonallergic angioedema without associated itching or urticaria may be hereditary (types I, II, and III) or acquiredV for example, associated with the use of an angiotensinconverting enzyme inhibitor or with malignancy. In an individual with angioedema who has no associated itching or hives, lack of response to H 1 antihistamine treatment points to the need for appropriate investigations for nonallergic (hereditary or acquired) angioedema (Table 4B). 13 Other H 1 antihistamines are widely used to relieve symptoms of upper respiratory tract infections, nonspecific cough, acute otitis media, otitis media with effusion, sinusitis, and nasal polyps; however, the published evidence does not support their use in these disorders (Table 4C). 36Y39

Central Nervous System and Vestibular System Disorders: The Unfavorable Therapeutic Index of First-Generation H 1 Antihistamines
Diphenhydramine, doxylamine, and pyrilamine are the most widely used sleep-inducing medications in the world (Table 4D). They are not, however, medications of choice for insomnia because they distort sleep architecture (as evidenced by a decrease in rapid eye movement sleep), increase rebound wakefulness, and potentially cause other adverse effects (Table 5). H 1 antihistamines are also still used for treatment of akathisia, serotonin syndrome, anxiety, migraine, and other CNS disorders. Diphenhydramine, hydroxyzine, cyproheptadine, and promethazine are still administered for perioperative sedation and for analgesia; however, there are serious concerns about their potential adverse effects in these settings. Indeed, promethazine has received a black box warning from the US FDA regarding its use in young children because of its association with CNS adverse effects, respiratory depression, and death in this age group. 2,3 For antiemetic effects and for prevention and treatment of motion sickness, vertigo, and related disorders, the firstgeneration H 1 antihistamines dimenhydrinate, diphenhydramine, meclizine, and promethazine are used to block the histaminergic signal from the vestibular nucleus to the vomiting center in the medulla. These medications have an unfavorable benefit-to-risk ratio, and because of CNS adverse effects, military pilots and commercial airline pilots are prohibited from using them. Second-generation H 1 antihistamines do not prevent motion sickness (Table 4E). 2,3

First-Generation H 1 Antihistamines
First-generation H 1 antihistamines potentially cause a wide variety of adverse effects in many body systems (Table 5). 2Y4,20,40 The main concern, however, is that all first-generation H 1 antihistamines, even when administered in manufacturers' recommended doses, have the proclivity to interfere with neurotransmission by histamine at CNS H 1 receptors. This potentially leads to adverse CNS symptoms such as drowsiness, sedation, somnolence, fatigue, and headache. More importantly, it potentially impairs cognitive function, memory, and psychomotor performance. Positron emission tomography with 11 C-doxepin as the positronemitting ligand reveals that these medications occupy more than 70% of the CNS H 1 receptors. 41 Blood-brain barrier penetration is related to their lipophilicity, relatively low molecular weights, and lack of substrate recognition by the Pglycoprotein efflux pump expressed on the luminal surfaces of nonfenestrated endothelial cells in the CNS vasculature. Central nervous system penetration is also documented in randomized controlled studies involving electroencephalographic monitoring, sleep latency measurements, and standardized performance tests ranging from simple reaction time tests to complex sensorimotor tasks, for example, computermonitored driving. 2Y4,10,42,43 Impairment of CNS function by first-generation H 1 antihistamines in usual doses has been documented in the absence of CNS symptoms. Tolerance to adverse CNS effects does not necessarily occur. After taking one of these older medications at bedtime, some individuals have residual CNS adverse effects the next morning, the so-called antihistamine hangover. The CNS effects of a first-generation H 1 antihistamine are similar to, and exacerbate, those produced by ethanol or by other CNS-active chemicals. 2,3 Prospective, long-term, randomized, controlled studies of the safety of these older H 1 antihistamines have never been published.

Second-Generation H 1 Antihistamines
In contrast, the newer H 1 antihistamines penetrate poorly into the CNS and occupy from 0% (fexofenadine, in doses up to 360 mg) to 30% (cetirizine, in above-label doses of 20 mg) of H 1 receptors in the CNS, as documented by positron emission tomographic scan studies. The results of these studies correlate well with electroencephalographic monitoring, including sleep latency tests, and with standardized performance tests. The second-generation H 1 antihistamines therefore have a low likelihood of causing CNS effects, although some of them, such as cetirizine and loratadine, potentially cause sedation when manufacturers' recommended Intranasal or ophthalmic formulations of H 1 antihistamines such as azelastine, emedastine, epinastine, levocabastine, ketotifen, and olopatadine have not been optimally studied using objective tests for adverse effects. They may cause stinging or burning upon application. Some of these formulations contain benzalkonium chloride 0.01%, which can dissolve contact lenses and should therefore be applied 10 minutes before insertion of lenses. Azelastine and emedastine may cause dysgeusia (bitter taste). § I Kr , rapid component of the delayed rectifier potassium current; I doses are exceeded. Fexofenadine, in off-label doses up to and including 360 mg daily, is the least sedating of these medications and is therefore considered to be the H 1 antihistamine of choice for airline pilots and people in other safety-critical jobs. 2Y4,10,42,43 The second-generation H 1 antihistamines do not exacerbate the CNS effects of coadministered alcohol or other CNSactive substances. In real-world prescription-event monitoring studies conducted in thousands of individuals with allergic rhinitis during the first 30 days after introduction of a new H 1 antihistamine in the United Kingdom, a low risk of sedation was reported for cetirizine, desloratadine, fexofenadine, levocetirizine, and loratadine. 44,45 The potential cardiac toxicity of H 1 antihistamines that occurs because of blockade of cardiac ion currents, most commonly the I Kr current, is not an H 1 antihistamine class effect. Since withdrawal of regulatory approval for astemizole and terfenadine almost 2 decades ago, the second-generation H 1 antihistamines remaining in use are free from potential cardiac adverse effects (Table 5). 2Y4 Randomized, controlled trials documenting the longterm safety of these medications have been published. These include randomized, controlled, masked studies of 6 to 12 months' duration with desloratadine, fexofenadine, and levocetirizine in adults, and of 12 to 18 months' duration with cetirizine, levocetirizine, and loratadine in very young children. 20,21,46Y48

H 1 -Antihistamine Overdoses
After overdose with a first-generation H 1 antihistamine, CNS symptoms predominate (Table 5). In adults, these symptoms usually culminate in extreme drowsiness, confusion, and coma. In infants and children, paradoxical CNS excitation, with symptoms of irritability, hyperactivity, insomnia, hallucinations, and seizures may occur. Some first-generation H 1 antihistamines also potentially cause dose-related cardiac adverse effects, including sinus tachycardia, reflex tachycardia, supraventricular arrhythmias, and after intentional large overdose, for example, diphenhydramine 0.5 to 1 g, prolongation of the QT interval with ventricular arrhythmias and torsade de pointes has been documented. 2Y5 Deaths attributed to first-generation H 1 antihistamines caused by accidental overdose, suicide, and homicide (of infants) have been reported in the literature for more than 6 decades. 40 Diphenhydramine overdoses are so frequently reported to poison control centers in the United States that evidence-based guidelines have been published to facilitate their management. 49 Massive (eg, up to 20-to 30-fold) overdoses of secondgeneration H 1 antihistamines such as cetirizine, fexofenadine, and loratadine have not been causally linked with serious CNS or cardiovascular adverse events or deaths (Table 5). 2,3,34 Use of H 1 Antihistamines in the Elderly Elderly people have increased vulnerability to adverse effects from any CNS-active chemical. Widespread use of first-generation H 1 antihistamines not only for allergic rhinoconjunctivitis and urticaria, but also for treatment of insomnia and other clinical problems is a particular concern because of their potential to cross the blood-brain barrier, impair neurotransmission at CNS H 1 receptors, and cause adverse CNS effects such as drowsiness, confusion, and agitation.
Polymedication is common in the elderly and the potential for first-generation H 1 antihistamines to interact with other drugs or herbal products is therefore increased in this age group. Potential antimuscarinic effects such as mydriasis, dry eyes and dry mouth, urinary retention, urinary hesitancy, and constipation, and potential antiY>-adrenergic effects such as dizziness and hypotension from first-generation H 1 antihistamines are also a concern (Table 5). 2Y4,20

Use of H 1 Antihistamines in Pregnancy and Lactation
Regulatory agencies such as the US FDA and the European Medicines Agency scrutinize all medications carefully for potential teratogenicity. No H 1 antihistamines have been designated as FDA Category A, denoting negative studies in animals and negative human data. A few H 1 antihistamines, including chlorpheniramine, diphenhydramine, cetirizine, levocetirizine, loratadine, and the ophthalmic formulation of emedastine, have been designated as FDA Category B. This denotes that either studies in animals have shown no adverse effects and data in humans are not available, or studies in animals have shown adverse effects but studies in humans have not shown these effects. These medications are therefore considered to be relatively safe for use if needed in pregnancy. Other H 1 antihistamines are designated as Category C. This denotes that either animal studies are positive and human data are not available, or neither animal nor human data are available. H 1 antihistamines that are not approved for use in the United States, for example, ebastine, mizolastine, and rupatadine are not categorized by the FDA (Table 5). 2,3 H 1 antihistamines are secreted into breast milk. Nursing infants receive approximately 0.1% of an orally administered maternal dose. First-generation H 1 antihistamines have been reported to cause sedation and other adverse effects in these infants (Table 5). 2,3

Use of H 1 Antihistamines in Infants and Young Children
First-generation H 1 antihistamines are widely used in infants and young children not only for allergic rhinoconjunctivitis and urticaria, but also for colds, cough, and other ailments, and for insomnia relief. Because of lack of efficacy data and concerns about safety, manufacturers in the United States and some other countries are being urged to voluntarily recall over-the-counter cold and cough preparations for children younger than 2 years and to add the warning, BDo not use to sedate children,[ to the label of first-generation H 1antihistamine preparations. 5,50 The second-generation H 1 antihistamines cetirizine, fexofenadine, and desloratadine have been prospectively studied in infants aged 6 to 11 months in placebo-controlled trials lasting a few weeks. 3 The long-term safety profiles of cetirizine, levocetirizine, and loratadine are similar to placebo, as confirmed in randomized, masked, controlled trials in young children aged 12 to 36 months. Studies of all 3 medications involved monitoring of adverse event reports, body mass and height measurements, blood hematology and chemistry tests, and for some of them, electrocardiograms, monitoring of developmental milestones and behavior, and objective tests of intellectual performance. 46Y48

SUMMARY AND FUTURE DIRECTIONS
The molecular basis for H 1 antihistamine action as inverse agonists rather than as antagonists or blockers has been briefly reviewed. The first-generation potentially sedating H 1 antihistamines, none of which have ever been optimally investigated in humans, have been described briefly. The secondgeneration nonsedating H 1 antihistamines, most of which are well investigated and are the H 1 antihistamines of choice for treatment of allergic rhinitis, allergic conjunctivitis, and chronic urticaria, have been discussed more extensively. In contrast to the first-generation H 1 antihistamines, the secondgeneration medications in the class are relatively free from adverse effects, including CNS and cardiac toxicity, when administered in standard doses and even if taken in overdose.
Most of the second-generation H 1 antihistamines currently in use have been identified by screening and structural modification of preexisting medications in the class. For example, cetirizine is a metabolite of hydroxyzine, levocetirizine is the active R-enantiomer of cetirizine, desloratadine is a metabolite of loratadine, and fexofenadine is a metabolite of terfenadine. New H 1 antihistamines continue to be developed and introduced for clinical use 51,52 ; however, such medications should be scrutinized closely because they may or may not represent important clinically relevant advances when compared with existing second-generation medications in the class. To date, no second-generation H 1 antihistamine appears to have superior overall efficacy to the others, although some are safer than others. 2Y4 The terms third generation, new generation, or next generation have been used to market some new H 1 antihistamines; however, this designation should be reserved for clinically advantageous H 1 antihistamines designed with the use of molecular techniques that might be available in the future. 4 Some of these medications might also have the intrinsic ability to down-regulate histamine at H 2 , H 3 , or H 4 receptors or to down-regulate leukotrienes or cytokines. 2Y4,32,53