H1 Antihistamines: Current Status and Future Directions
© World Allergy Organization; licensee BioMed Central Ltd. 2008
Received: 7 April 2008
Accepted: 16 July 2008
Published: 15 September 2008
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.
KeywordsH1 antihistamines second-generation H1 antihistamines nonsedating H1 antihistamines allergic rhinitis allergic conjunctivitis urticaria atopic dermatitis cetirizine desloratadine fexofenadine levocetirizine loratadine
Nerve cells, airway and vascular smooth muscle, endothelial cells, epithelial cells, neutrophils, eosinophils, monocytes/macrophages, DC, T and B cells, hepatocytes, chondrocytes
Nerve cells, airway and vascular smooth muscle, endothelial cells, epithelial cells, neutrophils, eosinophils, monocytes, DC, T and B cells, hepatocytes, Chondrocytes
High expression in histaminergic neurons, eosinophils, DC, monocytes; low expression in peripheral tissues
High expression on bone marrow and peripheral hematopoietic cells, eosinophils, neutrophils, DC, T cells, basophils, mast cells
Histamine function, General
↑ Pruritus, pain, vasodilation, vascular permeability, hypotension; flushing, headache, tachycardia, bronchoconstriction, stimulation of airway vagal afferent nerves and cough receptors; ↓ atrioventricular node conduction time
↑ Gastric acid secretion, vascular permeability, hypotension, flushing, headache, tachycardia, chronotropic and inotropic activity, bronchodilation, mucus production (airway)
↑ Pruritus (no mast cell involvement), ↑ nasal congestion; prevent excessive bronchoconstriction
↑ Pruritus (no mast cell involvement), ↑ nasal congestion; differentiation of myeloblasts and promyelocytes
Histamine function in allergic inflammation and immune modulation
↑ Release of histamine and other mediators; ↑ cellular adhesion molecule expression and chemotaxis of eosinophils and neutrophils; ↑ antigen-presenting cell capacity, costimulatory activity on B cells; ↑ cellular immunity (Th1), ↑ autoimmunity; ↓ humoral immunity and IgE production
↑ Eosinophil and neutrophil chemotaxis;↓ IL-12 by dendritic cells; ↑ IL-10 and development of Th2 or tolerance-inducing dendritic cells; ↑ humoral immunity;↓ cellular immunity; suppresses Th2 cells and cytokines; indirect role in allergy, autoimmunity, malignancy, graft rejection
Probably involved in control of neurogenic inflammation through local neuron-mast cell feedback loops; ↑ proinflammatory activity and APC capacity
↑ Calcium flux in human eosinophils; ↑ eosinophil chemotaxis; ↑ IL-16 production (H2 receptor also involved)
Histamine function in the CNS
Sleep/wakefulness, food intake, thermal regulation, emotions/aggressive behavior, locomotion, memory, learning
Presynaptic heteroreceptor; ↓ histamine, dopamine, serotonin, noradrenaline, and acetylcholine release
To be defined
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 H1 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-γ production, and down-regulates humoral immunity. Through the H2 receptor, it suppresses inflammatory and effector functions. Through the presynaptic H3 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 H4 receptor, it facilitates some proinflammatory activities (Table 1) .
Targeted disruption of the H1 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 H1 receptor-deficient have immunologic abnormalities, including impaired antigen-specific B-cell and T-cell responses [1–3].
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].
H1 antihistamines act as inverse agonists that combine with and stabilize the inactive conformation of the H1 receptor, shifting the equilibrium toward the inactive state. H1receptor polymorphisms have been described, although it is not yet clear how they influence the clinical response to H1 antihistamines. Human H1 receptors have approximately 45% homology with muscarinic receptors [2, 3].
H1 antihistamines down-regulate allergic inflammation through the H1 receptor, either directly or indirectly through nuclear factor-κB, 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, H1 antihistamines decrease mediator release; however, this effect is only seen at high H1-antihistamine concentrations .
H1 Antihistamines: Chemical and Functional Classification
Brompheniramine, chlorpheniramine, dimethindene,**,‡ pheniramine,‡ triprolidine*
Buclizine, cyclizine, hydroxyzine,* meclizine, oxatomide**
Azatadine, cyproheptadine, diphenylpyraline, ketotifen‡
Astemizole,** bilastine,** desloratadine,* ebastine,** fexofenadine,* levocabastine,‡ loratadine,* mizolastine,** olopatadine,‡ rupatadine,** terfenadine*,**
Carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, doxylamine, phenyltoloxamine**
Antazoline, pyrilamine, tripelennamine
Azelastine,‡ emedastine,‡ epinastine‡
H1 antihistamines, formerly known as H1 receptor antagonists or H1 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 H1 antihistamines are available worldwide. Health care professionals and consumers generally assume that all H1 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 second-generation H1 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 [2–4]. In this review, we compare the clinical pharmacology, efficacy, and safety of the first-generation H1 antihistamines with those of the second-generation H1 antihistamines.
Clinical pharmacology of H1antihistamines
Pharmacokinetics and Pharmacodynamics of Oral H1 Antihistamines Differ in Healthy Young Adults
H1 Antihistamine (Metabolite)
Time to Maximum Plasma Concentration (tmax, h) After a Single Dose
Terminal Elimination Half-life (t1/2, h)
Clinically Relevant Drug/Drug Interactions*
Onset/Duration of Action,** h
2.8 ± 0.8
27.9 ± 8.7
1.7 ± 1.0
9.2 ± 2.5
2.1 ± 0.4
20.0 ± 4.1
1.0 ± 0.5
0.8 ± 0.5
7 ± 1.5
1.2 ± 0.3 (1.5 ± 0.7)
7.8 ± 4.2 (24 ± 9.8)
Pharmacokinetics of second-generation H1antihistamines
For most of the second-generation H1 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 H1 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 [2–8].
Pharmacodynamics of second-generation H1antihistamines
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 H1 antihistamines . More commonly, however, the pharmacodynamics of H1 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 H1 antihistamines have been identified with regard to onset and intensity of action, time to peak effect, and duration of effect [2–8]. Wheal and flare suppression correlates better with tissue H1-antihistamine concentrations than with plasma H1-antihistamine concentrations, and correlates best with H1 receptor occupancy by free unbound drug, where such data are available [2, 3, 5–8, 10–12].
The onset of action of orally administered second-generation H1 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 H1 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, 5–8, 10, 11].
Pharmacokinetics and pharmacodynamics of intranasal and ophthalmic H1-antihistamine formulations
Pharmacokinetics and Pharmacodynamics of H1 Antihistamines for Intranasal/Ophthalmic Use
H1 Antihistamine (Metabolite)
Time to Maximum Plasma Concentration (tmax, h) After a Single Dose§
Terminal Elimination Half-Life (t1/2, h)§
Clinically Relevant Drug/Drug Interactions§
Onset/Duration of Action, h||
5.3 ± 1.6 (20.5)
22-27.6 (54 ± 15)
1.4 ± 0.5
Efficacy of H1antihistamines in allergic diseases
Diseases in Which Second-Generation H1 Antihistamines Are Drugs of First Choice Based on Randomized Controlled Trials (Grade of Recommendation = A)
In allergic rhinoconjunctivitis, second-generation H1 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 H1 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 H1 antihistamines has been investigated, no overall superior efficacy of one H1 antihistamine over another has been consistently documented. Additional comparative, randomized, controlled trials of second-generation H1 antihistamines are needed [2–5, 7, 8, 13–22].
Intranasal or ophthalmic H1-antihistamine formulations have a more rapid onset of action than oral H1-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, H1 antihistamines applied to the conjunctivae are the medications of choice not only for their antihistaminic effects, but also for their mast cell-stabilizing effects, and their rapid onset of action (range, 3-15 minutes). H1 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 H1 antihistamine for an individual with allergic rhinoconjunctivitis should be based on his/her preference for a particular H1-antihistamine formulation, route of administration, or dose regimen, and on considerations of potential benefits versus potential adverse effects.
Second-generation H1 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, H1 antihistamines are sometimes marketed in fixed-dose combinations with pseudoephedrine or other decongestants. H1 antihistamines are less efficacious than intranasal glucocorticoids, especially for relief of nasal congestion [2, 3, 14, 16].
H1 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, 23–29]. They are not efficacious in urticarial vasculitis.
In acute urticaria, both first-and second-generation H1 antihistamines are widely used, however, there are surprisingly few randomized controlled trials in support of this practice. In 2 different large, randomized, double-masked, placebo-controlled 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 [23–26].
The first-generation H1 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 H1 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, 27–29].
In chronic urticaria that is unresponsive to a second-generation H1 antihistamine in a standard dose, a variety of therapeutic strategies are recommended . High (off-label) doses of second-generation H1 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 H1 antihistamines on the same day or use of a nonsedating H1 antihistamine in the morning and a sedating H1 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 H1 antihistamines will respond to montelukast or to an H2 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, 23, 26].
Diseases in which H1 antihistamines are used but are not drugs of first choice
Diseases in Which H1 Antihistamines Are NOT Drugs of First Choice Based on Paucity of Evidence from Randomized Controlled Trials and on Availability of More Effective Alternatives*
Nonallergic (hereditary or acquired) angioedema
Diseases in Which H1 Antihistamines Are Used But Are Not Drugs of Choice Based on Lack of Evidence From Randomized Controlled Trials
Upper respiratory tract infection
Otitis media (acute otitis media, or otitis media with effusion)
CNS Diseases/Clinical Situations in Which First-Generation H1 Antihistamines Are Used*
Vestibular Disorders in Which First-Generation H1 Antihistamines Are Used*
Atopic dermatitis and other skin disorders
The evidence that H1 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 H1 receptors, but also through H3 and H4 receptors; in addition, cytokines such as interleukin-31 and other agents may be important pruritogens (Table 4B) [30–32].
The use of H1 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 .
Pretreatment with an H1 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. H1 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 house-dust 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].
A recent Cochrane collaboration review of 2070 studies of H1 antihistamines in anaphylaxis did not reveal any study that provided evidence for the use of H1 antihistamines in this disease. Individuals who require first-aid treatment of anaphylaxis occurring in a community setting should not depend on an oral H1 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) .
Nonallergic angioedema without associated itching or urticaria may be hereditary (types I, II, and III) or acquired--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) .
H1 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) [36–39].
Central nervous system and vestibular system disorders: the unfavorable therapeutic index of first-generation H1antihistamines
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). H1 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 first-generation H1 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 H1 antihistamines do not prevent motion sickness (Table 4E) [2, 3].
Adverse effects of H1antihistamines
Adverse Effects of First-Generation H1 Antihistamines Versus Second-Generation H1 Antihistamines
CNS (mechanism: interference with neurotransmitter effect of histamine through H1 receptor)
After usual doses, may cause drowsiness, fatigue, somnolence, dizziness, impairment of cognitive function, memory, and psychomotor performance, headache, dystonia, dyskinesia, agitation, confusion, and hallucinations.
None with fexofenadine at doses up to 360 mg (off label); none with desloratadine 5 mg or loratadine 10 mg, although dose-related CNS effects may occur at higher doses; cetirizine doses 10 mg or higher may cause sedation in adults.
May cause adverse CNS effects in newborns if taken by the mother immediately before parturition; may cause irritability, drowsiness, or respiratory depression in nursing infants
No CNS adverse effects reported in newborns or nursing infants
Cardiac§ (mechanisms: multiple; antimuscarinic effects; α-adrenergic receptor blockade; blockade of cardiac ion currents [IKr and, less commonly, INa, Ito, IKi, and IKs])
Dose-related sinus tachycardia; reflex tachycardia, prolonged atrial refractive period, and supraventricular arrhythmias; dose-related prolongation of the QTc interval and ventricular arrhythmias reported for cyproheptadine, diphenhydramine, doxepin, hydroxyzine, promethazine, and others
No major concerns in any country (such as the United States or Canada), in which regulatory approval was withdrawn for astemizole and terfenadine
Other sites (mechanisms: blockade of muscarinic, α-adrenergic, and serotonin receptors)
After usual doses: may cause mydriasis (pupillary dilation), dry eyes, dry mouth, urinary retention and hesitancy, decreased gastrointestinal motility, constipation, memory deficits; peripheral vasodilation, postural hypotension, dizziness; appetite stimulation and weight gain (cyproheptadine, ketotifen); contraindicated in individuals with glaucoma or prostatic hypertrophy
Toxicity after overdose (mechanisms: multiple)
CNS effects such as extreme drowsiness, lethargy, confusion, delirium, and coma in adults; paradoxical excitation, irritability, hyperactivity, insomnia, hallucinations, seizures, and respiratory depression/arrest in infants and young children; in both adults and children, CNS adverse effects predominate over cardiac adverse effects; death may occur within hours after ingestion of drug in untreated patients; rhabdomyolysis has also been reported
No serious toxicity or fatality reported
Abuse of drugs (mechanisms: through H1 and other receptors in the CNS)
Euphoria, hallucinations and "getting high" reported for diphenhydramine, dimenhydrinate, and others
Teratogenicity after use in pregnancy||
FDA Category B (chlorpheniramine, diphenhydramine) or C (hydroxyzine, ketotifen)
FDA Category B (cetirizine, emedastine, levocetrizine, loratadine) or C (azelastine, epinastine, desloratadine, fexofenadine, olopatadine)
None reported in humans
None documented in humans
Impairment of CNS function by first-generation H1 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 H1 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 H1 antihistamines have never been published.
In contrast, the newer H1 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 H1 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 H1 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 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 H1 antihistamine of choice for airline pilots and people in other safety-critica[2–4, 10, 42, 43]
The second-generation H1 antihistamines do not exacerbate the CNS effects of coadministered alcohol or other CNS-active 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 H1 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 H1 antihistamines that occurs because of blockade of cardiac ion currents, most commonly the IKr current, is not an H1 antihistamine class effect. Since withdrawal of regulatory approval for astemizole and terfenadine almost 2 decades ago, the second-generation H1 antihistamines remaining in use are free from potential cardiac adverse effects (Table 5) [2–4].
Randomized, controlled trials documenting the long-term 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, 46–48].
After overdose with a first-generation H1 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 H1 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 [2–5].
Deaths attributed to first-generation H1 antihistamines caused by accidental overdose, suicide, and homicide (of infants) have been reported in the literature for more than 6 decades . 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 .
Massive (eg, up to 20- to 30-fold) overdoses of second-generation H1 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 H1antihistamines in the elderly
Elderly people have increased vulnerability to adverse effects from any CNS-active chemical. Widespread use of first-generation H1 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 H1 receptors, and cause adverse CNS effects such as drowsiness, confusion, and agitation.
Polymedication is common in the elderly and the potential for first-generation H1 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 anti-α-adrenergic effects such as dizziness and hypotension from first-generation H1 antihistamines are also a concern (Table 5) [2–4, 20].
Use of H1antihistamines in pregnancy and lactation
Regulatory agencies such as the US FDA and the European Medicines Agency scrutinize all medications carefully for potential teratogenicity. No H1 antihistamines have been designated as FDA Category A, denoting negative studies in animals and negative human data. A few H1 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 H1 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. H1 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].
H1 antihistamines are secreted into breast milk. Nursing infants receive approximately 0.1% of an orally administered maternal dose. First-generation H1 antihistamines have been reported to cause sedation and other adverse effects in these infants (Table 5) [2, 3].
Use of H1antihistamines in infants and young children
First-generation H1 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, "Do not use to sedate children," to the label of first-generation H1-antihistamine preparations [5, 50].
The second-generation H1 antihistamines cetirizine, fexofenadine, and desloratadine have been prospectively studied in infants aged 6 to 11 months in placebo-controlled trials lasting a few weeks . 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 [46–48].
Summary and future directions
The molecular basis for H1 antihistamine action as inverse agonists rather than as antagonists or blockers has been briefly reviewed. The first-generation potentially sedating H1 antihistamines, none of which have ever been optimally investigated in humans, have been described briefly. The second-generation nonsedating H1 antihistamines, most of which are well investigated and are the H1 antihistamines of choice for treatment of allergic rhinitis, allergic conjunctivitis, and chronic urticaria, have been discussed more extensively. In contrast to the first-generation H1 antihistamines, the second-generation 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 H1 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 H1 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 H1 antihistamine appears to have superior overall efficacy to the others, although some are safer than others [2–4].
The terms third generation, new generation, or next generation have been used to market some new H1 antihistamines; however, this designation should be reserved for clinically advantageous H1 antihistamines designed with the use of molecular techniques that might be available in the future . Some of these medications might also have the intrinsic ability to down-regulate histamine at H2, H3, or H4 receptors or to down-regulate leukotrienes or cytokines [2–4, 32, 53].
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