Advances in H1-Antihistamines
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《新英格兰医药杂志》
More than 30,000 peer-reviewed articles on histamine and the H1-antihistamines have been published since this subject was last reviewed in the Journal a decade ago.1 The role of histamine in neurotransmission,2,3,4 allergic inflammation,5,6,7,8,9,10,11,12 and immune modulation9,10,11,12,13,14,15,16,17,18,19 has been further elucidated since that time. The human H1-histamine and H2-histamine receptors were cloned and characterized in the early 1990s,20,21 as were the human H3-histamine and H4-histamine receptors several years ago.22,23
H1-antihistamines, historically known as histamine H1-receptor blockers or antagonists, are specific for the H1-receptor. In addition, some H1-antihistamines inhibit transmission through the muscarinic, -adrenergic, and serotonin receptors and through ion channels (Figure 1).24,25,26 The H1-antihistamines have recently been reclassified as inverse agonists, rather than as H1-receptor antagonists, which is consonant with an increased understanding of their molecular pharmacologic features (Figure 2). 24,25 More than 40 H1-antihistamines are available worldwide — indeed, these agents are among the most widely used of all medications.27 The H1-antihistamines astemizole and terfenadine, which are associated with cardiac toxic effects,25 are no longer approved for use. New H1-antihistamines have been developed and introduced.26,28 Both health care professionals and consumers generally assume that all approved H1-antihistamines have been shown to be efficacious and safe, but many medications in this class, in particular those introduced before 1985, have not been optimally studied in randomized, double-blind, controlled trials. This discussion of the differences in the clinical pharmacology and the similarities in efficacy and safety of the H1-antihistamines25,26,29,30 is based on a review of the literature published since 1994.
Figure 1. Benefits and Potential Adverse Effects of H1-Antihistamines.
H1-antihistamines down-regulate allergic inflammation mainly through the H1-receptor. They potentially cause adverse effects not only through H1-receptors in the central nervous system but also through the muscarinic, -adrenergic, and serotonin receptors and cardiac ion channels. Blue arrows refer to actions through the H1-receptor, and red arrows to actions through other receptors and through ion channels. IKr denotes the rapid component of the delayed rectifier potassium current.
Figure 2. Simplified Two-State Model of the Histamine H1-Receptor.
In Panel A, the inactive state of the histamine H1-receptor is in equilibrium with the active state. In Panel B, an agonist, which has a preferential affinity for the active state, stabilizes the receptor in this conformation and consequently causes a shift in the equilibrium toward the active state. In Panel C, an inverse agonist, which has a preferential affinity for the inactive state, stabilizes the receptor in this conformation and consequently causes a shift in the equilibrium toward the inactive state. All known H1-antihistamines function as inverse agonists. Intracellular and extracellular are defined in relation to the cell membrane. The purple serpentine line denotes the G-protein–coupled receptor, and green the cell membrane. Adapted from Leurs et al.25
Histamine
Role in Human Health
Histamine, a natural body constituent, is a low-molecular-weight amine synthesized from L-histidine exclusively by histidine decarboxylase, an enzyme that is expressed in cells throughout the body, including central nervous system neurons, gastric-mucosa parietal cells, mast cells, and basophils. Histamine has an important role in human health, exerting its diverse biologic effects through four types of receptors (Table 1).1,10,11,12,20,21,22,23 It is involved in the proliferation and differentiation of cells, hematopoiesis, embryonic development, regeneration, and wound healing. In the mammalian central nervous system, histamine is produced in neurons that have cell bodies located exclusively in the tuberomamillary nucleus of the posterior hypothalamus with axons that transmit histamine to the frontal and temporal cortexes and other regions of the brain. In this phylogenetically "old" neurotransmitter system, histamine is involved in the regulation of basic body functions through the H1-receptor. These functions include the cycle of sleeping and waking, energy and endocrine homeostasis, cognition, and memory. Histamine also possesses anticonvulsant activity.2,4 It modulates the release of neurotransmitters through presynaptic H3-receptors located on histaminergic and nonhistaminergic neurons of the central and peripheral nervous system.22 Histamine facilitates some proinflammatory activities through the novel H4-receptor, which has a high degree of homology with the H3-receptor but a unique expression profile.23
Table 1. Characteristics of the Histamine Receptors.
Allergic Inflammation and Immune Modulation
Histamine plays a pivotal role in allergic inflammation, which is a complex network of cellular events that involve redundant mediators and signals. Histamine is released from the granules of FcRI+ cells (e.g., mast cells and basophils) along with tryptase and other preformed mediators, as well as leukotrienes, prostaglandins, and other newly generated mediators, after the cross-linking of surface IgE by allergen or through mechanisms that are independent of IgE. After allergen challenge in sensitized persons, histamine is found locally in relatively large (microgram) quantities per 1 million cells, in contrast to leukotrienes and other mediators, which are found in picogram quantities. Although most of the effects of histamine in allergic disease occur through H1 receptors5,10,11,12 (Table 1), hypotension, tachycardia, flushing, and headache occur through both the H1- and H2-receptors in the vasculature,6 whereas cutaneous itch and nasal congestion may occur through both the H1- and H3-receptors.7,8 In addition to its role in the early allergic response to antigen, histamine acts as a stimulatory signal for the production of cytokines and the expression of cell-adhesion molecules and class II antigens, thereby contributing to the late allergic response.9,10,11
Histamine exerts other important immunomodulatory effects through H1-, H2-, H3-, and H4-receptors9,10,11,12,13,14,15,16,17,18,19 (Table 1). The expression of the receptors changes according to the stage of cell differentiation and microenvironmental influences. Depending on the predominance of the type of histamine receptor and on the experimental system studied, histamine may have proinflammatory or antiinflammatory effects. Through the H1-receptor, histamine has proinflammatory activity and is involved in the development of several aspects of antigen-specific immune response, including the maturation of dendritic cells and the modulation of the balance of type 1 helper (Th1) T cells and type 2 helper (Th2) T cells. Histamine may induce an increase in the proliferation of Th1 cells and in the production of interferon and may block humoral immune responses by means of this mechanism. Histamine also induces the release of proinflammatory cytokines and lysosomal enzymes from human macrophages and has the capacity to influence the activity of basophils, eosinophils, and fibroblasts. In addition, it may play a role in autoimmunity and malignant disease through the H1-receptor.10,18
Types of Histamine Receptors
The four major types of histamine receptor, H1-, H2-, H3-, and H4-receptors, differ in their expression, signal transduction, and function10,11,12,20,21,22,23,24 (Table 1). H1- and H2-receptors are widely expressed, in contrast to H3- and H4-receptors. All types of histamine receptor are heptahelical transmembrane molecules that transduce extracellular signals by way of G proteins to intracellular second-messenger systems. All have constitutive activity, which is defined as the ability to trigger downstream events even in the absence of ligand binding (Figure 2).24,25 The active and inactive states of the receptors exist in equilibrium. H1-receptor polymorphisms have been described, although it is not yet clear how they influence the clinical response to H1-antihistamines.31 Human H1-receptors have approximately 45 percent homology with muscarinic receptors. Targeted disruption of the H1-receptor gene in mice results in the impairment of neurologic functions such as memory, learning, and locomotion and in aggressive behavior. Mice that are H1-receptor–deficient also have immunologic abnormalities, including impaired antigen-specific responses of T cells and B cells.19,32
Basic and Clinical Pharmacology
Inverse Agonism and Classification Systems
H1-antihistamines act as inverse agonists that combine with and stabilize the inactive form of the H1-receptor, shifting the equilibrium toward the inactive state24,25 (Figure 2). Traditionally, these agents have been classified into six chemical groups: the ethanolamines, ethylenediamines, alkylamines, piperazines, piperidines, and phenothiazines. The classification according to function of first-generation H1-antihistamines, which are sedating, as compared with second-generation compounds, which are relatively nonsedating, is now more commonly used1,26 (Table 2). Many of the H1-antihistamines introduced during the past two decades have been identified by means of the screening of existing compounds, and they are chemically related to older medications in the class. For example, acrivastine is related to triprolidine, 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. No currently available H1-antihistamine is appropriately described as "third" or "new" generation — these terms should be reserved for future H1-antihistamines that will be designed with the use of molecular techniques.33
Table 2. Chemical and Functional Classification of H1-Antihistamines.
Antiallergic and Antiinflammatory Activities
The antiallergic and antiinflammatory activities of H1-antihistamines occur through a variety of mechanisms15,24,25,34,35,36 (Figure 1). Antiallergic activities such as the inhibition of the release of mediators from mast cells and basophils probably involve a direct inhibitory effect on calcium-ion channels that reduces the inward calcium current activated by the depletion of the intracellular store of calcium. Antiinflammatory effects such as the inhibition of the expression of cell adhesion molecules and the chemotaxis of eosinophils and other cells may involve down-regulation of the H1-receptor–activated nuclear factor-B, a ubiquitous transcription factor that binds to the promoter and enhancer regions of many genes that regulate the production of proinflammatory cytokines and adhesion proteins.24,25
Pretreatment with an oral H1-antihistamine reduces the early response to an allergen challenge in the conjunctiva, nose, lower airway, and skin. In patients who receive such pretreatment, the level of proinflammatory cell adhesion molecules (e.g., intercellular adhesion molecules and vascular cell adhesion molecules), cells (e.g., eosinophils and neutrophils), cytokines, and mediators (e.g., histamine, leukotrienes, prostaglandins, and others) is lower in lavage fluid after the challenge than at baseline. Plasma exudation is also diminished, a change that is reflected in decreases in the levels of albumin, fucose, and 2-macroglobulin. Physiological changes and relief from symptoms can be measured concurrently. Moreover, pretreatment of the nasal mucosa and the conjunctivae with topical H1-antihistamines down-regulates the inflammation locally after an allergen challenge.26,36
In order to establish the clinical relevance of the antiinflammatory effects of the H1-antihistamines to their overall efficacy, further studies conducted during natural exposure to allergens are needed to document that the levels of proinflammatory cell adhesion molecules, cells, cytokines, and mediators decrease in response to the usual doses of these medications. Additional studies comparing the antiinflammatory effects of different H1-antihistamines are also needed. Glucocorticoids, irrespective of the route of administration, consistently show greater antiinflammatory effects than H1-antihistamines do.26
Pharmacokinetics and Pharmacodynamics
Clinical pharmacologic studies provide objective information on which to base doses and dose intervals of the H1-antihistamines, including the modified dose regimens that may be required to treat children and elderly persons, patients with hepatic or renal dysfunction, or those who take other medications concurrently. The pharmacokinetics and pharmacodynamics of the H1-antihistamines are summarized in Table 3.1,28,33,37,38,39,40,41 Many first-generation H1-antihistamines have never been adequately studied in healthy adults, let alone in special populations or with respect to drug–drug interactions.37,38 All first-generation H1-antihistamines, and some second-generation H1-antihistamines such as desloratadine and loratadine are metabolized by the hepatic cytochrome P450 (CYP450) system. Cetirizine is excreted largely unchanged in the urine, and fexofenadine is excreted largely unchanged in the feces.
Table 3. Pharmacokinetics and Pharmacodynamics of Oral H1-Antihistamines in Healthy Young Adults.
Drug–drug interactions may involve interference with absorption through active transport mechanisms (e.g., P-glycoprotein, organic-anion transporters, and other ATP-binding cassette transporters) in the mucosa of the gastrointestinal tract, or may involve the inhibition or induction of metabolism in the hepatic CYP450 system. Interactions that result in decreased H1-antihistamine plasma concentrations may be associated with diminished efficacy. Interactions that result in increased plasma concentrations may be more likely to be associated with adverse effects when first-generation H1-antihistamines are used than when second-generation H1-antihistamines, which have a wider therapeutic index,29,30 are used.
The onset, the amount, and the duration of action of H1-antihistamine can be studied by measuring the suppression of the symptoms of allergic rhinitis in groups of patients who have been challenged with high doses of allergen indoors and out of season, or who have been challenged naturally outdoors during the peak pollen season.42,43 More commonly, the pharmacodynamics of orally administered H1-antihistamines are investigated by measuring the suppression of the cutaneous histamine-induced or allergen-induced wheal and flare,37,38,39,40,41 which is reported to correlate with H1-antihistamine concentrations in the skin.37,41 Clinically relevant differences in the onset, amount, and duration of action can be identified37,38,39,40,41 (Table 3). After a single oral dose, the onset of action occurs within one to three hours. The duration of action for many oral H1-antihistamines is at least 24 hours, facilitating once-daily dosing. No tolerance to the suppressive effect on skin-test reactivity to allergens has been found in rigorously controlled, double-blind studies of three months' duration. Residual suppression of skin-test reactivity to allergens lasts for up to seven days after discontinuation of an H1-antihistamine that was in regular use for one or more weeks.37
Although topical intranasal and ophthalmic H1-antihistamines differ in their pharmacokinetics, most of them need to be administered twice daily because of washout from the nasal mucosa or conjunctivae. Dose adjustment is not required in special populations. Some systemic absorption, and transient suppression of skin-test reactivity, may occur.
Adverse Effects
First-generation H1-antihistamines such as chlorpheniramine, diphenhydramine, hydroxyzine, and promethazine bind to H1-receptors and block the neurotransmitter effect of histamine in the central nervous system (Figure 1 and Table 4). The ability of these medications to penetrate the blood–brain barrier is related to their lipophilicity, relatively low molecular weight, and lack of recognition by the P-glycoprotein efflux pump that is expressed on the luminal surfaces of nonfenestrated endothelial cells in the vasculature of the central nervous system.44,45,46 Positron-emission tomography (PET) with 11C doxepin as the radioactive ligand has shown that the first-generation H1-antihistamines occupy 50 to 90 percent of the H1-receptors in the frontal cortex, temporal cortex, hippocampus, and pons.47
Table 4. Potential Adverse Effects of H1-Antihistamines.
Second-generation H1-antihistamines are specific for H1-receptors and penetrate the central nervous system poorly, owing to their lipophobicity and affinity for P-glycoprotein that is expressed on vascular endothelial cells in the central nervous system.44,45,46 Their propensity to occupy central nervous system H1-receptors varies from none for fexofenadine to 30 percent for cetirizine.48
Cardiac toxic effects induced by H1-antihistamines occur rarely and independently of the H1-receptor49,50,51 and are not a class effect25,51 (Figure 1 and Table 4). First-generation H1-antihistamines have antimuscarinic and -adrenergic blockade activity and may cause dose-related prolongation of the QT interval. Two early second-generation H1-antihistamines, astemizole and terfenadine, which are no longer approved, block the rapid component of delayed rectifier potassium current (IKr) with 50 percent inhibitory concentrations in the nanomolar range. As a result, these two agents potentially prolong the monophasic cardiac action potential and QT interval, induce the development of early after-depolarizations and dispersion (slowing) of repolarization, and thereby may cause torsades de pointes. New second-generation H1-antihistamines such as cetirizine, desloratadine, fexofenadine, and loratadine have 50 percent inhibitory concentrations in the micromolar range and have a thousandth of the potency in blocking the IKr current.25,49,50,51
Efficacy
First-generation H1-antihistamines have not been optimally studied in any allergic disorder. Indeed, most clinical trials of these older medications do not meet current standards with regard to study design (e.g., criteria for randomization, controls, masking, measured outcomes, number of participants enrolled, reporting of attrition, adherence, and duration). In contrast, the use of second-generation H1-antihistamines for the relief of symptoms in seasonal and perennial allergic rhinoconjunctivitis and in chronic urticaria is supported by a large number of adequately powered, randomized, double-blind, placebo-controlled clinical trials lasting weeks or months.52,53,54
H1-antihistamines are best taken on a regular basis, rather than as needed, in order to reduce allergic inflammation and prevent symptoms.36 Tolerance to doses that achieve clinical efficacy does not develop.26,55,56 The dose–response curve for efficacy is flat as compared with that for adverse effects, especially with the use of first-generation H1-antihistamines. The relief from symptoms may be incomplete, however, because leukotrienes and other mediators also play a role in allergic inflammation.
Allergic Rhinoconjunctivitis
H1-antihistamines relieve nasal itching, sneezing, rhinorrhea, and congestion; conjunctival itching, watering, and redness; and itching of the palate, throat, and ears. These agents thus reduce misery and improve the quality of life.53,55,56,57,58,59,60,61,62 Various H1-antihistamines have a similar efficacy for the overall relief of symptoms reported by patients53,57,58,59; statistically significant differences reported in the relief of individual symptoms are small and inconsistent.58,59 Topical intranasal or ophthalmic H1-antihistamines have a more rapid onset of action than oral H1-antihistamines, but they require administration several times a day.53 The selection of an H1-antihistamine for a patient should be based primarily on considerations of safety26,53 and the patient's preference for a particular medication, formulation, route of administration, or dose regimen. There are not many comparative data on these drugs, and more head-to-head comparisons among H1-antihistamines are needed.
Many H1-antihistamines are available in fixed-dose formulations in combination with pseudoephedrine,61 which enhances the relief of nasal congestion. The efficacy of H1-antihistamines is similar to or greater than that of topical cromoglycate or nedocromil and similar to that of the leukotriene antagonist montelukast.53,62 An oral H1-antihistamine administered alone or with a leukotriene antagonist appears to be less effective than an intranasal glucocorticoid.63,64
Other Airway Disorders
Although the H1-antihistamines are widely used to relieve symptoms in upper respiratory tract infections, otitis media, and sinusitis, the published evidence does not support this practice.53,65,66 Similarly, current evidence does not support the use of H1-antihistamines in persistent asthma.53,67 However, in patients with allergic inflammation throughout the upper and lower airways that results in concurrent symptoms of allergic rhinitis and asthma, the use of H1-antihistamines is reported to result in a significant decrease in the symptoms of both rhinitis and asthma as well as a decrease in the use of 2-adrenergic–agonist medications, and the H1-antihistamines may even improve pulmonary function.55,61,68 Among these patients, desloratadine and montelukast appear to have similar effects.68 Treatment with cetirizine over a period of 18 months is reported to delay the onset of asthma in some young children with atopic dermatitis who are at high risk for the disease,69 but this observation requires confirmation.
Urticaria
H1-antihistamines reduce the number, size, and duration of wheals and decrease itching. They are efficacious in relieving and preventing acute urticaria,54,70,71 although there is considerably less published evidence in support of their efficacy in this disorder as compared with chronic urticaria,54,72,73,74,75,76 in which the second-generation H1-antihistamines cetirizine, desloratadine, fexofenadine, and loratadine have been well studied. Both first-generation and second-generation H1-antihistamines appear to have similar efficacy in chronic urticaria,74 but additional comparative studies are needed. Although the sequential use of two different H1-antihistamines within the same day (i.e., one medication in the morning and another at bedtime) has been recommended,72 this strategy has not been adequately tested in randomized, double-blind, placebo-controlled trials. H1-antihistamines appear to be effective in treating dermatographism and physical urticarias, including cholinergic, cold, and pressure-induced urticarias, but they do not seem to be effective in treating either urticarial vasculitis or hereditary angioedema.54,73 In some patients with chronic urticaria, an H2-antihistamine such as cimetidine administered concurrently with an H1-antihistamine may give added relief and appears to be worth a trial of a period of three to four weeks.54,72,73 A recent study showed that the simultaneous administration of the leukotriene antagonist montelukast did not appear to offer an advantage over the H1-antihistamine desloratadine alone.76
Other Allergic and Immunologic Disorders
H1-antihistamines should not replace epinephrine in the treatment of severe acute systemic allergic reactions (anaphylaxis). However, administered as an ancillary treatment, alone or with an H2-antihistamine, these agents may relieve flushing, itching, urticaria, and rhinorrhea.77 Furthermore, they are used, often in combination with other medications, to prevent idiopathic anaphylaxis, reactions to allergen-specific immunotherapy, and reactions to radiocontrast agents.77,78
H1-antihistamines are used both for relief of itching and for their glucocorticoid-sparing effects in atopic dermatitis, but the evidence in support of their efficacy in this disorder is not convincing.79,80,81 They are also administered to treat symptoms in disorders such as mastocytosis and local allergic reactions to insect bites.26,82,83
Disorders of the Central Nervous System and Vestibular Disorders
Although they are not the medications of choice, the first-generation H1-antihistamines diphenhydramine, doxylamine, and pyrilamine are widely used in the treatment of insomnia,84,85 and diphenhydramine, hydroxyzine, cyproheptadine, and promethazine remain in use for perioperative sedation86 and for analgesia,87 akathisia,88 serotonin syndrome, anxiety, and other conditions affecting the central nervous system.26 Dimenhydrinate, diphenhydramine, meclizine, and promethazine block the histaminergic signal from the vestibular nucleus to the vomiting center in the medulla and are thus administered for antiemetic effects89 and for the prevention and treatment of motion sickness, vertigo, and related disorders.26 The unfavorable risk:benefit ratio associated with the use of first-generation H1-antihistamines to treat disorders of the central nervous system and vestibular disorders has been noted,84,85,86,90 and their use is contraindicated in the treatment of pilots, ships' captains, drivers, and others who must remain alert.
Potential Adverse Effects
The first-generation H1-antihistamines, in the usual doses, have potential adverse effects (Table 4). Although some of these medications have been in clinical use for six decades, no long-term safety studies have been published. These older medications have the potential to lead to depression of the central nervous system, have been associated with fatalities in accidental or intentional overdose, and are potential agents of suicide and of homicide of infants.51,91,92,93,94,95,96 Some first-generation H1-antihistamines are drugs of abuse.97
In contrast, second-generation H1-antihistamines are relatively free of adverse effects29,30,38,40 and appear to have relatively few toxic effects in the setting of overdose.98,99,100 The results of a prospective safety study of the use of cetirizine in the treatment of infants101 and an 18-month safety study of cetirizine in young children100,102 are available. Additional safety studies in infants, the elderly, and other vulnerable populations and additional long-term safety studies are needed.
Central Nervous System Toxicity
There are few regulations to protect consumers from potential toxic effects on the central nervous system from H1-antihistamines (Table 4). Indeed, people purchasing over-the-counter first-generation H1-antihistamines are on their own with regard to reading and comprehending the warnings and the abbreviated list of potential adverse effects on the labels of the packages. Moreover, neither standardized objective testing nor the precise quantification of symptoms related to the central nervous system is required by regulatory agencies during the preclinical and clinical development of new H1-antihistamines.
People may fail to recognize or may underestimate the adverse effects on the central nervous system resulting from the use of H1-antihistamines — a situation analogous to that with other sedating medications and with chemicals such as ethanol. Lapses and errors may be documented when patients who do not report symptoms undergo objective testing of the functioning of the central nervous system after ingestion of an H1-antihistamine.29,30
In the more than 80 randomized, double-blind, placebo-controlled, comparative crossover studies that have been performed, statistically significant and clinically relevant differences between the effects of first-generation and second-generation H1-antihistamines have been consistently documented.29,30,40,103,104,105,106,107 In addition to the PET scans described earlier,47,48 multiple tests of sleep latency, evoked potentials, and other electroencephalographic studies, as well as tests of psychomotor performance, have been conducted. The tests range from simple tasks (e.g., critical flicker-fusion tests or digit–symbol substitution) to complex sensorimotor tasks (e.g., simulated flying or driving and actual on-the-road driving).29,30,40,103,104,105,106,107 The interpretation of most of these studies is complicated by the fact that they were conducted in healthy young adults rather than in persons with allergic rhinoconjunctivitis or urticaria — conditions that are associated with the daytime sedation due to nocturnal symptoms and sleep deprivation.
Small body mass and the consequent large dose for size of H1-antihistamine, hepatic or renal dysfunction leading to accumulation in the central nervous system, and the concomitant use of drugs or chemicals such as alcohol that impair the function of the central nervous system may increase the risk of adverse effects, especially with regard to the use of first-generation H1-antihistamines.29,30,105,106 Driving performance is reported to be impaired more by diphenhydramine than by alcohol.106 In a randomized, placebo-controlled trial with the use of a driving simulator, a 50-mg dose of diphenhydramine impaired driving performance to a greater extent than alcohol; the alcohol dose produced an estimated blood alcohol concentration of 0.1 percent (21.7 mmol per liter).106 The use of potentially sedating H1-antihistamines is a particular concern in the treatment of elderly persons107 and anyone with obvious or subclinical cognitive impairment. This is also true for those with jobs that require constant alertness.108 First-generation H1-antihistamines have been implicated in the loss of productivity by workers,109 injuries,110 and deaths in aviation and traffic accidents.111 Military and civilian pilots are prohibited from using these or any other potentially sedating medications before or during flights. Currently, desloratadine, fexofenadine, and loratadine are the only oral H1-antihistamines for which pilots can receive a waiver for use from the Federal Aviation Administration.
Taking a first-generation H1-antihistamine at bedtime may result in a hangover (i.e., impaired cognitive and psychomotor performance with or without perceptible sedation) the following morning.112 Clinical tolerance to the sedating effects of first-generation H1-antihistamines, which has been reported anecdotally but has not consistently been found on objective testing, is an important issue that deserves further exploration.113,114 Additional investigations are also needed in people with allergic rhinitis or urticaria, the elderly, elite athletes, and children, about whom there are conflicting data regarding the effects of H1-antihistamines on performance tests.115,116
Cardiac Toxicity
There is an increased risk of cardiac toxic effects from the use of any H1-antihistamine that prolongs the QT interval in women and in patients with preexisting organic heart disease (e.g., ischemia or cardiomyopathy), cardiac arrhythmias (congenital or acquired, including bradycardia), or electrolyte imbalance (i.e., hypokalemia, hypocalcemia, and hypomagnesemia). Also at an increased risk are persons who take overdoses or ingest foods, medications, or herbal formulations that inhibit the elimination of H1-antihistamines and increase their concentrations in cardiac tissue. In addition, persons concomitantly taking another drug that blocks the IKr current are at increased risk.26,49,50,51
During the preclinical and early clinical development of new drugs, regulatory agencies worldwide now aim to identify all new medications, including H1-antihistamines, that may block the IKr current, prolong the QT interval, and potentially cause polymorphic ventricular arrhythmias. Second-generation H1-antihistamines such as cetirizine, desloratadine, fexofenadine, and loratadine appear to be relatively free of cardiac toxic effects as compared with astemizole and terfenadine26,49,50,100,101,117 (Table 4). The human ether-a-go-go–related gene (HERG) encodes for the alpha subunit of the IKr current, and if a medication is implicated in triggering ventricular arrhythmias in a given person, it may now be possible to confirm or rule out causality by performing in vitro tests involving variants of cloned HERG IKr current.118
Other Adverse Effects and Concerns
In rare cases, both first- and second-generation H1-antihistamines are reported to cause adverse effects, the mechanisms for which are incompletely understood.26 These effects include fixed-drug eruption, photosensitivity, urticaria, fever, elevation of liver enzymes and hepatitis, and agranulocytosis. First-generation H1-antihistamines such as diphenhydramine or doxepin, applied topically to abraded or excoriated skin, may cause systemic adverse effects or contact dermatitis. Topical intranasal or ophthalmic H1-antihistamines may cause stinging or burning. Azelastine and emedastine may cause dysgeusia (bitter taste). No H1-antihistamines currently approved for use in the United States are considered to have carcinogenic or tumor-promoting effects in humans.119 First-generation H1-antihistamines, particularly those in the phenothiazine class, have been associated with the sudden infant death syndrome, although causality has never been proved. Some oral H1-antihistamines, including cetirizine and loratadine, are considered relatively safe for use during pregnancy (Food and Drug Administration category B) (Table 4).120
Future Directions
Through the H1-receptor, histamine has an important role as a chemical messenger in physiologic responses, including neurotransmission, and in allergic inflammation and immunomodulation. Health care professionals and people who are attempting to make a rational selection from among the large number of H1-antihistamines available should be aware that many medications in this class have never been optimally investigated. Most H1-antihistamines have similar efficacy in allergic rhinoconjunctivitis and chronic urticaria; however, there are clinically relevant differences in their pharmacologic characteristics and their safety profiles. Additional within-class comparative studies of their efficacy and safety are needed. To protect people from the toxic effects of H1-antihistamines on the central nervous system, regulatory agencies should consider developing guidelines for measuring the penetration of the blood–brain barrier and its clinical sequelae, analogous to those being developed to protect people from cardiac toxic effects. In the future, on the basis of improved knowledge of ligand–receptor interactions, clinically advantageous H1-antihistamines designed with the use of molecular techniques, perhaps with intrinsic H2-, H3-, or H4-antihistamine or antileukotriene properties, may be developed.
Dr. Simons reports having received grant support, through the University of Manitoba, from Dynavax Technologies, Merck Frosst Canada, Schering Canada, and UCB Pharma.
I am indebted to C.A. Akdis, R. Leurs, and K.J. Simons for helpful discussions.
Source Information
From the Section of Allergy and Clinical Immunology, Department of Pediatrics and Child Health, Department of Immunology, and the Canadian Institutes of Health Research National Allergy and Asthma Training Program, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Address reprint requests to Dr. Simons at 820 Sherbrook St., Winnipeg, MB R3A 1R9, Canada, or at lmcniven@hsc.mb.ca.
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H1-antihistamines, historically known as histamine H1-receptor blockers or antagonists, are specific for the H1-receptor. In addition, some H1-antihistamines inhibit transmission through the muscarinic, -adrenergic, and serotonin receptors and through ion channels (Figure 1).24,25,26 The H1-antihistamines have recently been reclassified as inverse agonists, rather than as H1-receptor antagonists, which is consonant with an increased understanding of their molecular pharmacologic features (Figure 2). 24,25 More than 40 H1-antihistamines are available worldwide — indeed, these agents are among the most widely used of all medications.27 The H1-antihistamines astemizole and terfenadine, which are associated with cardiac toxic effects,25 are no longer approved for use. New H1-antihistamines have been developed and introduced.26,28 Both health care professionals and consumers generally assume that all approved H1-antihistamines have been shown to be efficacious and safe, but many medications in this class, in particular those introduced before 1985, have not been optimally studied in randomized, double-blind, controlled trials. This discussion of the differences in the clinical pharmacology and the similarities in efficacy and safety of the H1-antihistamines25,26,29,30 is based on a review of the literature published since 1994.
Figure 1. Benefits and Potential Adverse Effects of H1-Antihistamines.
H1-antihistamines down-regulate allergic inflammation mainly through the H1-receptor. They potentially cause adverse effects not only through H1-receptors in the central nervous system but also through the muscarinic, -adrenergic, and serotonin receptors and cardiac ion channels. Blue arrows refer to actions through the H1-receptor, and red arrows to actions through other receptors and through ion channels. IKr denotes the rapid component of the delayed rectifier potassium current.
Figure 2. Simplified Two-State Model of the Histamine H1-Receptor.
In Panel A, the inactive state of the histamine H1-receptor is in equilibrium with the active state. In Panel B, an agonist, which has a preferential affinity for the active state, stabilizes the receptor in this conformation and consequently causes a shift in the equilibrium toward the active state. In Panel C, an inverse agonist, which has a preferential affinity for the inactive state, stabilizes the receptor in this conformation and consequently causes a shift in the equilibrium toward the inactive state. All known H1-antihistamines function as inverse agonists. Intracellular and extracellular are defined in relation to the cell membrane. The purple serpentine line denotes the G-protein–coupled receptor, and green the cell membrane. Adapted from Leurs et al.25
Histamine
Role in Human Health
Histamine, a natural body constituent, is a low-molecular-weight amine synthesized from L-histidine exclusively by histidine decarboxylase, an enzyme that is expressed in cells throughout the body, including central nervous system neurons, gastric-mucosa parietal cells, mast cells, and basophils. Histamine has an important role in human health, exerting its diverse biologic effects through four types of receptors (Table 1).1,10,11,12,20,21,22,23 It is involved in the proliferation and differentiation of cells, hematopoiesis, embryonic development, regeneration, and wound healing. In the mammalian central nervous system, histamine is produced in neurons that have cell bodies located exclusively in the tuberomamillary nucleus of the posterior hypothalamus with axons that transmit histamine to the frontal and temporal cortexes and other regions of the brain. In this phylogenetically "old" neurotransmitter system, histamine is involved in the regulation of basic body functions through the H1-receptor. These functions include the cycle of sleeping and waking, energy and endocrine homeostasis, cognition, and memory. Histamine also possesses anticonvulsant activity.2,4 It modulates the release of neurotransmitters through presynaptic H3-receptors located on histaminergic and nonhistaminergic neurons of the central and peripheral nervous system.22 Histamine facilitates some proinflammatory activities through the novel H4-receptor, which has a high degree of homology with the H3-receptor but a unique expression profile.23
Table 1. Characteristics of the Histamine Receptors.
Allergic Inflammation and Immune Modulation
Histamine plays a pivotal role in allergic inflammation, which is a complex network of cellular events that involve redundant mediators and signals. Histamine is released from the granules of FcRI+ cells (e.g., mast cells and basophils) along with tryptase and other preformed mediators, as well as leukotrienes, prostaglandins, and other newly generated mediators, after the cross-linking of surface IgE by allergen or through mechanisms that are independent of IgE. After allergen challenge in sensitized persons, histamine is found locally in relatively large (microgram) quantities per 1 million cells, in contrast to leukotrienes and other mediators, which are found in picogram quantities. Although most of the effects of histamine in allergic disease occur through H1 receptors5,10,11,12 (Table 1), hypotension, tachycardia, flushing, and headache occur through both the H1- and H2-receptors in the vasculature,6 whereas cutaneous itch and nasal congestion may occur through both the H1- and H3-receptors.7,8 In addition to its role in the early allergic response to antigen, histamine acts as a stimulatory signal for the production of cytokines and the expression of cell-adhesion molecules and class II antigens, thereby contributing to the late allergic response.9,10,11
Histamine exerts other important immunomodulatory effects through H1-, H2-, H3-, and H4-receptors9,10,11,12,13,14,15,16,17,18,19 (Table 1). The expression of the receptors changes according to the stage of cell differentiation and microenvironmental influences. Depending on the predominance of the type of histamine receptor and on the experimental system studied, histamine may have proinflammatory or antiinflammatory effects. Through the H1-receptor, histamine has proinflammatory activity and is involved in the development of several aspects of antigen-specific immune response, including the maturation of dendritic cells and the modulation of the balance of type 1 helper (Th1) T cells and type 2 helper (Th2) T cells. Histamine may induce an increase in the proliferation of Th1 cells and in the production of interferon and may block humoral immune responses by means of this mechanism. Histamine also induces the release of proinflammatory cytokines and lysosomal enzymes from human macrophages and has the capacity to influence the activity of basophils, eosinophils, and fibroblasts. In addition, it may play a role in autoimmunity and malignant disease through the H1-receptor.10,18
Types of Histamine Receptors
The four major types of histamine receptor, H1-, H2-, H3-, and H4-receptors, differ in their expression, signal transduction, and function10,11,12,20,21,22,23,24 (Table 1). H1- and H2-receptors are widely expressed, in contrast to H3- and H4-receptors. All types of histamine receptor are heptahelical transmembrane molecules that transduce extracellular signals by way of G proteins to intracellular second-messenger systems. All have constitutive activity, which is defined as the ability to trigger downstream events even in the absence of ligand binding (Figure 2).24,25 The active and inactive states of the receptors exist in equilibrium. H1-receptor polymorphisms have been described, although it is not yet clear how they influence the clinical response to H1-antihistamines.31 Human H1-receptors have approximately 45 percent homology with muscarinic receptors. Targeted disruption of the H1-receptor gene in mice results in the impairment of neurologic functions such as memory, learning, and locomotion and in aggressive behavior. Mice that are H1-receptor–deficient also have immunologic abnormalities, including impaired antigen-specific responses of T cells and B cells.19,32
Basic and Clinical Pharmacology
Inverse Agonism and Classification Systems
H1-antihistamines act as inverse agonists that combine with and stabilize the inactive form of the H1-receptor, shifting the equilibrium toward the inactive state24,25 (Figure 2). Traditionally, these agents have been classified into six chemical groups: the ethanolamines, ethylenediamines, alkylamines, piperazines, piperidines, and phenothiazines. The classification according to function of first-generation H1-antihistamines, which are sedating, as compared with second-generation compounds, which are relatively nonsedating, is now more commonly used1,26 (Table 2). Many of the H1-antihistamines introduced during the past two decades have been identified by means of the screening of existing compounds, and they are chemically related to older medications in the class. For example, acrivastine is related to triprolidine, 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. No currently available H1-antihistamine is appropriately described as "third" or "new" generation — these terms should be reserved for future H1-antihistamines that will be designed with the use of molecular techniques.33
Table 2. Chemical and Functional Classification of H1-Antihistamines.
Antiallergic and Antiinflammatory Activities
The antiallergic and antiinflammatory activities of H1-antihistamines occur through a variety of mechanisms15,24,25,34,35,36 (Figure 1). Antiallergic activities such as the inhibition of the release of mediators from mast cells and basophils probably involve a direct inhibitory effect on calcium-ion channels that reduces the inward calcium current activated by the depletion of the intracellular store of calcium. Antiinflammatory effects such as the inhibition of the expression of cell adhesion molecules and the chemotaxis of eosinophils and other cells may involve down-regulation of the H1-receptor–activated nuclear factor-B, a ubiquitous transcription factor that binds to the promoter and enhancer regions of many genes that regulate the production of proinflammatory cytokines and adhesion proteins.24,25
Pretreatment with an oral H1-antihistamine reduces the early response to an allergen challenge in the conjunctiva, nose, lower airway, and skin. In patients who receive such pretreatment, the level of proinflammatory cell adhesion molecules (e.g., intercellular adhesion molecules and vascular cell adhesion molecules), cells (e.g., eosinophils and neutrophils), cytokines, and mediators (e.g., histamine, leukotrienes, prostaglandins, and others) is lower in lavage fluid after the challenge than at baseline. Plasma exudation is also diminished, a change that is reflected in decreases in the levels of albumin, fucose, and 2-macroglobulin. Physiological changes and relief from symptoms can be measured concurrently. Moreover, pretreatment of the nasal mucosa and the conjunctivae with topical H1-antihistamines down-regulates the inflammation locally after an allergen challenge.26,36
In order to establish the clinical relevance of the antiinflammatory effects of the H1-antihistamines to their overall efficacy, further studies conducted during natural exposure to allergens are needed to document that the levels of proinflammatory cell adhesion molecules, cells, cytokines, and mediators decrease in response to the usual doses of these medications. Additional studies comparing the antiinflammatory effects of different H1-antihistamines are also needed. Glucocorticoids, irrespective of the route of administration, consistently show greater antiinflammatory effects than H1-antihistamines do.26
Pharmacokinetics and Pharmacodynamics
Clinical pharmacologic studies provide objective information on which to base doses and dose intervals of the H1-antihistamines, including the modified dose regimens that may be required to treat children and elderly persons, patients with hepatic or renal dysfunction, or those who take other medications concurrently. The pharmacokinetics and pharmacodynamics of the H1-antihistamines are summarized in Table 3.1,28,33,37,38,39,40,41 Many first-generation H1-antihistamines have never been adequately studied in healthy adults, let alone in special populations or with respect to drug–drug interactions.37,38 All first-generation H1-antihistamines, and some second-generation H1-antihistamines such as desloratadine and loratadine are metabolized by the hepatic cytochrome P450 (CYP450) system. Cetirizine is excreted largely unchanged in the urine, and fexofenadine is excreted largely unchanged in the feces.
Table 3. Pharmacokinetics and Pharmacodynamics of Oral H1-Antihistamines in Healthy Young Adults.
Drug–drug interactions may involve interference with absorption through active transport mechanisms (e.g., P-glycoprotein, organic-anion transporters, and other ATP-binding cassette transporters) in the mucosa of the gastrointestinal tract, or may involve the inhibition or induction of metabolism in the hepatic CYP450 system. Interactions that result in decreased H1-antihistamine plasma concentrations may be associated with diminished efficacy. Interactions that result in increased plasma concentrations may be more likely to be associated with adverse effects when first-generation H1-antihistamines are used than when second-generation H1-antihistamines, which have a wider therapeutic index,29,30 are used.
The onset, the amount, and the duration of action of H1-antihistamine can be studied by measuring the suppression of the symptoms of allergic rhinitis in groups of patients who have been challenged with high doses of allergen indoors and out of season, or who have been challenged naturally outdoors during the peak pollen season.42,43 More commonly, the pharmacodynamics of orally administered H1-antihistamines are investigated by measuring the suppression of the cutaneous histamine-induced or allergen-induced wheal and flare,37,38,39,40,41 which is reported to correlate with H1-antihistamine concentrations in the skin.37,41 Clinically relevant differences in the onset, amount, and duration of action can be identified37,38,39,40,41 (Table 3). After a single oral dose, the onset of action occurs within one to three hours. The duration of action for many oral H1-antihistamines is at least 24 hours, facilitating once-daily dosing. No tolerance to the suppressive effect on skin-test reactivity to allergens has been found in rigorously controlled, double-blind studies of three months' duration. Residual suppression of skin-test reactivity to allergens lasts for up to seven days after discontinuation of an H1-antihistamine that was in regular use for one or more weeks.37
Although topical intranasal and ophthalmic H1-antihistamines differ in their pharmacokinetics, most of them need to be administered twice daily because of washout from the nasal mucosa or conjunctivae. Dose adjustment is not required in special populations. Some systemic absorption, and transient suppression of skin-test reactivity, may occur.
Adverse Effects
First-generation H1-antihistamines such as chlorpheniramine, diphenhydramine, hydroxyzine, and promethazine bind to H1-receptors and block the neurotransmitter effect of histamine in the central nervous system (Figure 1 and Table 4). The ability of these medications to penetrate the blood–brain barrier is related to their lipophilicity, relatively low molecular weight, and lack of recognition by the P-glycoprotein efflux pump that is expressed on the luminal surfaces of nonfenestrated endothelial cells in the vasculature of the central nervous system.44,45,46 Positron-emission tomography (PET) with 11C doxepin as the radioactive ligand has shown that the first-generation H1-antihistamines occupy 50 to 90 percent of the H1-receptors in the frontal cortex, temporal cortex, hippocampus, and pons.47
Table 4. Potential Adverse Effects of H1-Antihistamines.
Second-generation H1-antihistamines are specific for H1-receptors and penetrate the central nervous system poorly, owing to their lipophobicity and affinity for P-glycoprotein that is expressed on vascular endothelial cells in the central nervous system.44,45,46 Their propensity to occupy central nervous system H1-receptors varies from none for fexofenadine to 30 percent for cetirizine.48
Cardiac toxic effects induced by H1-antihistamines occur rarely and independently of the H1-receptor49,50,51 and are not a class effect25,51 (Figure 1 and Table 4). First-generation H1-antihistamines have antimuscarinic and -adrenergic blockade activity and may cause dose-related prolongation of the QT interval. Two early second-generation H1-antihistamines, astemizole and terfenadine, which are no longer approved, block the rapid component of delayed rectifier potassium current (IKr) with 50 percent inhibitory concentrations in the nanomolar range. As a result, these two agents potentially prolong the monophasic cardiac action potential and QT interval, induce the development of early after-depolarizations and dispersion (slowing) of repolarization, and thereby may cause torsades de pointes. New second-generation H1-antihistamines such as cetirizine, desloratadine, fexofenadine, and loratadine have 50 percent inhibitory concentrations in the micromolar range and have a thousandth of the potency in blocking the IKr current.25,49,50,51
Efficacy
First-generation H1-antihistamines have not been optimally studied in any allergic disorder. Indeed, most clinical trials of these older medications do not meet current standards with regard to study design (e.g., criteria for randomization, controls, masking, measured outcomes, number of participants enrolled, reporting of attrition, adherence, and duration). In contrast, the use of second-generation H1-antihistamines for the relief of symptoms in seasonal and perennial allergic rhinoconjunctivitis and in chronic urticaria is supported by a large number of adequately powered, randomized, double-blind, placebo-controlled clinical trials lasting weeks or months.52,53,54
H1-antihistamines are best taken on a regular basis, rather than as needed, in order to reduce allergic inflammation and prevent symptoms.36 Tolerance to doses that achieve clinical efficacy does not develop.26,55,56 The dose–response curve for efficacy is flat as compared with that for adverse effects, especially with the use of first-generation H1-antihistamines. The relief from symptoms may be incomplete, however, because leukotrienes and other mediators also play a role in allergic inflammation.
Allergic Rhinoconjunctivitis
H1-antihistamines relieve nasal itching, sneezing, rhinorrhea, and congestion; conjunctival itching, watering, and redness; and itching of the palate, throat, and ears. These agents thus reduce misery and improve the quality of life.53,55,56,57,58,59,60,61,62 Various H1-antihistamines have a similar efficacy for the overall relief of symptoms reported by patients53,57,58,59; statistically significant differences reported in the relief of individual symptoms are small and inconsistent.58,59 Topical intranasal or ophthalmic H1-antihistamines have a more rapid onset of action than oral H1-antihistamines, but they require administration several times a day.53 The selection of an H1-antihistamine for a patient should be based primarily on considerations of safety26,53 and the patient's preference for a particular medication, formulation, route of administration, or dose regimen. There are not many comparative data on these drugs, and more head-to-head comparisons among H1-antihistamines are needed.
Many H1-antihistamines are available in fixed-dose formulations in combination with pseudoephedrine,61 which enhances the relief of nasal congestion. The efficacy of H1-antihistamines is similar to or greater than that of topical cromoglycate or nedocromil and similar to that of the leukotriene antagonist montelukast.53,62 An oral H1-antihistamine administered alone or with a leukotriene antagonist appears to be less effective than an intranasal glucocorticoid.63,64
Other Airway Disorders
Although the H1-antihistamines are widely used to relieve symptoms in upper respiratory tract infections, otitis media, and sinusitis, the published evidence does not support this practice.53,65,66 Similarly, current evidence does not support the use of H1-antihistamines in persistent asthma.53,67 However, in patients with allergic inflammation throughout the upper and lower airways that results in concurrent symptoms of allergic rhinitis and asthma, the use of H1-antihistamines is reported to result in a significant decrease in the symptoms of both rhinitis and asthma as well as a decrease in the use of 2-adrenergic–agonist medications, and the H1-antihistamines may even improve pulmonary function.55,61,68 Among these patients, desloratadine and montelukast appear to have similar effects.68 Treatment with cetirizine over a period of 18 months is reported to delay the onset of asthma in some young children with atopic dermatitis who are at high risk for the disease,69 but this observation requires confirmation.
Urticaria
H1-antihistamines reduce the number, size, and duration of wheals and decrease itching. They are efficacious in relieving and preventing acute urticaria,54,70,71 although there is considerably less published evidence in support of their efficacy in this disorder as compared with chronic urticaria,54,72,73,74,75,76 in which the second-generation H1-antihistamines cetirizine, desloratadine, fexofenadine, and loratadine have been well studied. Both first-generation and second-generation H1-antihistamines appear to have similar efficacy in chronic urticaria,74 but additional comparative studies are needed. Although the sequential use of two different H1-antihistamines within the same day (i.e., one medication in the morning and another at bedtime) has been recommended,72 this strategy has not been adequately tested in randomized, double-blind, placebo-controlled trials. H1-antihistamines appear to be effective in treating dermatographism and physical urticarias, including cholinergic, cold, and pressure-induced urticarias, but they do not seem to be effective in treating either urticarial vasculitis or hereditary angioedema.54,73 In some patients with chronic urticaria, an H2-antihistamine such as cimetidine administered concurrently with an H1-antihistamine may give added relief and appears to be worth a trial of a period of three to four weeks.54,72,73 A recent study showed that the simultaneous administration of the leukotriene antagonist montelukast did not appear to offer an advantage over the H1-antihistamine desloratadine alone.76
Other Allergic and Immunologic Disorders
H1-antihistamines should not replace epinephrine in the treatment of severe acute systemic allergic reactions (anaphylaxis). However, administered as an ancillary treatment, alone or with an H2-antihistamine, these agents may relieve flushing, itching, urticaria, and rhinorrhea.77 Furthermore, they are used, often in combination with other medications, to prevent idiopathic anaphylaxis, reactions to allergen-specific immunotherapy, and reactions to radiocontrast agents.77,78
H1-antihistamines are used both for relief of itching and for their glucocorticoid-sparing effects in atopic dermatitis, but the evidence in support of their efficacy in this disorder is not convincing.79,80,81 They are also administered to treat symptoms in disorders such as mastocytosis and local allergic reactions to insect bites.26,82,83
Disorders of the Central Nervous System and Vestibular Disorders
Although they are not the medications of choice, the first-generation H1-antihistamines diphenhydramine, doxylamine, and pyrilamine are widely used in the treatment of insomnia,84,85 and diphenhydramine, hydroxyzine, cyproheptadine, and promethazine remain in use for perioperative sedation86 and for analgesia,87 akathisia,88 serotonin syndrome, anxiety, and other conditions affecting the central nervous system.26 Dimenhydrinate, diphenhydramine, meclizine, and promethazine block the histaminergic signal from the vestibular nucleus to the vomiting center in the medulla and are thus administered for antiemetic effects89 and for the prevention and treatment of motion sickness, vertigo, and related disorders.26 The unfavorable risk:benefit ratio associated with the use of first-generation H1-antihistamines to treat disorders of the central nervous system and vestibular disorders has been noted,84,85,86,90 and their use is contraindicated in the treatment of pilots, ships' captains, drivers, and others who must remain alert.
Potential Adverse Effects
The first-generation H1-antihistamines, in the usual doses, have potential adverse effects (Table 4). Although some of these medications have been in clinical use for six decades, no long-term safety studies have been published. These older medications have the potential to lead to depression of the central nervous system, have been associated with fatalities in accidental or intentional overdose, and are potential agents of suicide and of homicide of infants.51,91,92,93,94,95,96 Some first-generation H1-antihistamines are drugs of abuse.97
In contrast, second-generation H1-antihistamines are relatively free of adverse effects29,30,38,40 and appear to have relatively few toxic effects in the setting of overdose.98,99,100 The results of a prospective safety study of the use of cetirizine in the treatment of infants101 and an 18-month safety study of cetirizine in young children100,102 are available. Additional safety studies in infants, the elderly, and other vulnerable populations and additional long-term safety studies are needed.
Central Nervous System Toxicity
There are few regulations to protect consumers from potential toxic effects on the central nervous system from H1-antihistamines (Table 4). Indeed, people purchasing over-the-counter first-generation H1-antihistamines are on their own with regard to reading and comprehending the warnings and the abbreviated list of potential adverse effects on the labels of the packages. Moreover, neither standardized objective testing nor the precise quantification of symptoms related to the central nervous system is required by regulatory agencies during the preclinical and clinical development of new H1-antihistamines.
People may fail to recognize or may underestimate the adverse effects on the central nervous system resulting from the use of H1-antihistamines — a situation analogous to that with other sedating medications and with chemicals such as ethanol. Lapses and errors may be documented when patients who do not report symptoms undergo objective testing of the functioning of the central nervous system after ingestion of an H1-antihistamine.29,30
In the more than 80 randomized, double-blind, placebo-controlled, comparative crossover studies that have been performed, statistically significant and clinically relevant differences between the effects of first-generation and second-generation H1-antihistamines have been consistently documented.29,30,40,103,104,105,106,107 In addition to the PET scans described earlier,47,48 multiple tests of sleep latency, evoked potentials, and other electroencephalographic studies, as well as tests of psychomotor performance, have been conducted. The tests range from simple tasks (e.g., critical flicker-fusion tests or digit–symbol substitution) to complex sensorimotor tasks (e.g., simulated flying or driving and actual on-the-road driving).29,30,40,103,104,105,106,107 The interpretation of most of these studies is complicated by the fact that they were conducted in healthy young adults rather than in persons with allergic rhinoconjunctivitis or urticaria — conditions that are associated with the daytime sedation due to nocturnal symptoms and sleep deprivation.
Small body mass and the consequent large dose for size of H1-antihistamine, hepatic or renal dysfunction leading to accumulation in the central nervous system, and the concomitant use of drugs or chemicals such as alcohol that impair the function of the central nervous system may increase the risk of adverse effects, especially with regard to the use of first-generation H1-antihistamines.29,30,105,106 Driving performance is reported to be impaired more by diphenhydramine than by alcohol.106 In a randomized, placebo-controlled trial with the use of a driving simulator, a 50-mg dose of diphenhydramine impaired driving performance to a greater extent than alcohol; the alcohol dose produced an estimated blood alcohol concentration of 0.1 percent (21.7 mmol per liter).106 The use of potentially sedating H1-antihistamines is a particular concern in the treatment of elderly persons107 and anyone with obvious or subclinical cognitive impairment. This is also true for those with jobs that require constant alertness.108 First-generation H1-antihistamines have been implicated in the loss of productivity by workers,109 injuries,110 and deaths in aviation and traffic accidents.111 Military and civilian pilots are prohibited from using these or any other potentially sedating medications before or during flights. Currently, desloratadine, fexofenadine, and loratadine are the only oral H1-antihistamines for which pilots can receive a waiver for use from the Federal Aviation Administration.
Taking a first-generation H1-antihistamine at bedtime may result in a hangover (i.e., impaired cognitive and psychomotor performance with or without perceptible sedation) the following morning.112 Clinical tolerance to the sedating effects of first-generation H1-antihistamines, which has been reported anecdotally but has not consistently been found on objective testing, is an important issue that deserves further exploration.113,114 Additional investigations are also needed in people with allergic rhinitis or urticaria, the elderly, elite athletes, and children, about whom there are conflicting data regarding the effects of H1-antihistamines on performance tests.115,116
Cardiac Toxicity
There is an increased risk of cardiac toxic effects from the use of any H1-antihistamine that prolongs the QT interval in women and in patients with preexisting organic heart disease (e.g., ischemia or cardiomyopathy), cardiac arrhythmias (congenital or acquired, including bradycardia), or electrolyte imbalance (i.e., hypokalemia, hypocalcemia, and hypomagnesemia). Also at an increased risk are persons who take overdoses or ingest foods, medications, or herbal formulations that inhibit the elimination of H1-antihistamines and increase their concentrations in cardiac tissue. In addition, persons concomitantly taking another drug that blocks the IKr current are at increased risk.26,49,50,51
During the preclinical and early clinical development of new drugs, regulatory agencies worldwide now aim to identify all new medications, including H1-antihistamines, that may block the IKr current, prolong the QT interval, and potentially cause polymorphic ventricular arrhythmias. Second-generation H1-antihistamines such as cetirizine, desloratadine, fexofenadine, and loratadine appear to be relatively free of cardiac toxic effects as compared with astemizole and terfenadine26,49,50,100,101,117 (Table 4). The human ether-a-go-go–related gene (HERG) encodes for the alpha subunit of the IKr current, and if a medication is implicated in triggering ventricular arrhythmias in a given person, it may now be possible to confirm or rule out causality by performing in vitro tests involving variants of cloned HERG IKr current.118
Other Adverse Effects and Concerns
In rare cases, both first- and second-generation H1-antihistamines are reported to cause adverse effects, the mechanisms for which are incompletely understood.26 These effects include fixed-drug eruption, photosensitivity, urticaria, fever, elevation of liver enzymes and hepatitis, and agranulocytosis. First-generation H1-antihistamines such as diphenhydramine or doxepin, applied topically to abraded or excoriated skin, may cause systemic adverse effects or contact dermatitis. Topical intranasal or ophthalmic H1-antihistamines may cause stinging or burning. Azelastine and emedastine may cause dysgeusia (bitter taste). No H1-antihistamines currently approved for use in the United States are considered to have carcinogenic or tumor-promoting effects in humans.119 First-generation H1-antihistamines, particularly those in the phenothiazine class, have been associated with the sudden infant death syndrome, although causality has never been proved. Some oral H1-antihistamines, including cetirizine and loratadine, are considered relatively safe for use during pregnancy (Food and Drug Administration category B) (Table 4).120
Future Directions
Through the H1-receptor, histamine has an important role as a chemical messenger in physiologic responses, including neurotransmission, and in allergic inflammation and immunomodulation. Health care professionals and people who are attempting to make a rational selection from among the large number of H1-antihistamines available should be aware that many medications in this class have never been optimally investigated. Most H1-antihistamines have similar efficacy in allergic rhinoconjunctivitis and chronic urticaria; however, there are clinically relevant differences in their pharmacologic characteristics and their safety profiles. Additional within-class comparative studies of their efficacy and safety are needed. To protect people from the toxic effects of H1-antihistamines on the central nervous system, regulatory agencies should consider developing guidelines for measuring the penetration of the blood–brain barrier and its clinical sequelae, analogous to those being developed to protect people from cardiac toxic effects. In the future, on the basis of improved knowledge of ligand–receptor interactions, clinically advantageous H1-antihistamines designed with the use of molecular techniques, perhaps with intrinsic H2-, H3-, or H4-antihistamine or antileukotriene properties, may be developed.
Dr. Simons reports having received grant support, through the University of Manitoba, from Dynavax Technologies, Merck Frosst Canada, Schering Canada, and UCB Pharma.
I am indebted to C.A. Akdis, R. Leurs, and K.J. Simons for helpful discussions.
Source Information
From the Section of Allergy and Clinical Immunology, Department of Pediatrics and Child Health, Department of Immunology, and the Canadian Institutes of Health Research National Allergy and Asthma Training Program, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Address reprint requests to Dr. Simons at 820 Sherbrook St., Winnipeg, MB R3A 1R9, Canada, or at lmcniven@hsc.mb.ca.
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