REVIEW
`
` CURRENTOPINION Ophthalmic antihistamines and H1–H4 receptors
`
`Laurie Wadea, Leonard Bielorya,b,c, and Shara Rudnera,d
`
`Purpose of review
`Antihistamines exert pharmacologic effects by binding to four histamine receptors (H1–H4) at different
`affinities, producing variable effects depending on the receptor they predominantly bind to. This review’s
`purpose is to determine the relative potency of antihistamines by comparing their binding affinities to these
`receptors. Studies on binding affinities of antihistamines to histamine receptors were reviewed and the
`dissociation constant for inhibitor binding (Ki) analyzed to determine the most and least potent
`antihistamine for each receptor.
`
`Recent findings
`We retrieved the binding affinities for nineteen antihistamines. For H1 receptors, pyrilamine exhibited the
`highest affinity (Ki¼ 0.8 nM), and thioperamide the lowest (Ki¼ 280 000 nM). For H2 receptors, ranitidine
`exhibited the highest affinity (Ki¼ 187 nM), and olopatadine the lowest (Ki¼ 100 000 nM). For the recently
`discovered H3 and H4 receptors, thioperamide exhibited the highest affinity (Ki¼ 1.1 nM), and olopatadine
`exhibited the lowest (Ki¼ 79 400 nM), to H3. Data on binding affinities to the H4 receptor exist for:
`ketotifen, pheniramine, ranitidine, cimetidine and thioperamide. Of these, thioperamide exhibited the
`highest affinity (Ki¼ 27 nM), whereas cimetidine and ranitidine exhibited the lowest affinity
`(Ki¼ >10 000 nM) for H4 receptors.
`Summary
`This review summarizes the relative potency of antihistamines based on their binding affinities to the four
`histamine receptors. Although data on binding affinities of antihistamines to the H4 receptor are sparse, it is
`apparent that further research on these histamine subtypes may open new venues for more direct treatment
`with a higher therapeutic efficacy on allergic disorders including those affecting the ocular surface.
`
`Keywords
`allergic conjunctivitis, antihistamine, histamine, histamine receptors, ophthalmic
`
`INTRODUCTION
`Allergic conjunctivitis, associated with ocular symp-
`toms such as itching, redness and swelling of the
`conjunctiva and increased tear production, affects
`up to 40% of the population, with an increase in
`incidence over the past 10 years [1&]. Antihistamines
`act as an inverse agonist on the histamine receptor,
`and thus primarily block the acute phase allergic
`response, but differ due to their affinity and prefer-
`ence for each of the various histamine receptors, and
`their efficacy depends largely on their ability to bind
`to the receptor responsible for that symptom. Mast
`cell stabilizers prevent the release of inflammatory
`mediators associated with the late phase of the
`allergic response. Topical ophthalmic drugs that
`work both as antihistamines and mast cell stabilizers
`have become a preferred treatment because of their
`dual action and, at times, multiple actions. Even
`among antihistamines that bind preferentially to
`the same receptor, there is variation in binding
`affinity. The purpose of this review is to determine
`the relative potency of different antihistamines by
`
`comparing the binding affinity of each antihist-
`amine to each of the four histamine receptors [2].
`
`ANTIHISTAMINE VARIATION
`The efficacy of an antihistamine depends mostly on
`four factors: the drug’s binding affinity for each of
`the different histamine receptors, the rate of onset
`of the drug binding to the receptor, the duration of
`binding and maintenance of the drug-receptor com-
`plex. The additive qualities of each of these factors
`determine how useful a specific drug will be at
`
`aRutgers University, New Brunswick, New Jersey, bRobert Wood
`Johnson University Hospital New Brunswick, cSTARx Allergy and Asthma
`Center, Springfield and dBelvidere Pharmacy, Highland Park, New Jersey,
`USA
`
`Correspondence to Shara Rudner, 440 A Raritan Ave, Highland Park, NJ
`08904, USA. Tel: +1 908 756 6695/202; e-mail: shara@belviderephar
`macy.com
`Curr Opin Allergy Clin Immunol 2012, 12:510–516
`
`DOI:10.1097/ACI.0b013e328357d3ba
`
`Volume 12  Number 5  October 2012
`www.co-allergy.com
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
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`
`KEY POINTS
` A relative potency of marketed antihistamines to each
`of the four known histamine receptors (H1–H4) can be
`determined by comparing the binding affinity of a drug
`to each receptor.
` The ideal antihistamine would have high affinity for the
`targeted histamine receptor (high efficacy), with low
`affinity for muscarinic receptors (low incidence of side
`effects).
` Alcaftadine, a novel topical antihistamine used for the
`treatment of allergic conjunctivitis, has antagonistic
`activity against both the H1 and H4 histamine
`receptor types.
` Further research into the activity of various
`antihistamines and their activity at the H4 receptor is
`needed to determine what future place this receptor
`may have in the treatment of allergic and inflammatory
`disease states.
`
`antagonizing the histamine receptor, including its
`efficacy, length of duration of histamine blockade,
`and relief of symptoms while minimizing side
`effects.
`
`BINDING AFFINITY
`Antihistamines are believed to work by binding to
`the active site of the receptor, thereby blocking
`access of histamine. In order to achieve inhibition,
`enough of the drug has to be present to prevent the
`activation of the receptor. If a drug has poor binding
`affinity, a higher concentration of drug is needed to
`achieve inhibition compared with a drug that has
`high binding affinity. Additionally, if a drug has a
`lower binding affinity for the receptor than hista-
`mine itself, theoretically it might require large
`amounts of drug to outcompete histamine for the
`receptor site. A comparison of a drug’s binding
`affinity for the targeted histamine receptor in
`relation to other antihistamines is useful to predict
`how potent its antihistaminic effect will be [3].
`
`RATE OF ONSET OF DRUG-RECEPTOR
`INTERACTION/DURATION OF DRUG-
`RECEPTOR COMPLEXES
`The competition between drug and histamine is a
`dynamic process through time. Both drug and his-
`tamine constantly bind to and release from the
`receptor. The sum total of which compound spends
`more time ‘occupying’ the binding site will deter-
`mine whether the overall effect on the receptor will
`be stimulation (by histamine) or inhibition (by
`
`Ophthalmic antihistamines and H1 H4 receptors Wade et al.
`
`drug). Two properties that could enhance the
`efficacy of an antihistamine are: rapid equilibrium
`and onset of action, and slow dissociation rate from
`the receptor.
`
`SIDE-EFFECT PROFILE
`Many antihistamines are known to have anticholi-
`nergic effects that may cause ocular drying through
`muscarinic receptor inhibition. In some cases, anti-
`cholinergic side effects are used favorably for symp-
`tomatic relief, such as the case of diphenhydramine
`in the treatment of insomnia or excessive allergic
`rhinorrhea.
`
`HISTAMINE RECEPTOR TYPES
`Histamine affects nearly every human organ and
`has a broad range of biological functions that are
`mediated through the distribution of four types of
`G-coupled histamine receptors. The effects of hista-
`mine binding to different histamine receptors vary
`based on the location of the receptor and the physio-
`logical responses with which it is associated. All four
`receptors have some constitutive (ongoing) activity,
`even without histamine bound. The histamine H1
`and H2 receptors are much more widely expressed
`throughout the body than H3 and H4.
`All histamine receptors are heptahelical trans-
`membrane molecules that transduce extracellular
`signals by way of G proteins to intracellular second
`messenger systems. These second messenger sys-
`tems include Ca2þ
`, cGMP in H1 receptors, cAMP
`in H2 receptors and Ca2þ
`and MAP kinase for H3
`and H4 receptors. The effect histamine has is largely
`dependent on the expression of specific histamine
`receptors on different cell types and the location of
`these receptors in different physiological locations
`[2]. A summary of histamine receptor types and
`related effects is shown in Table 1.
`
`Table 1. Histamine receptor types and associated
`effects
`
`H1
`
`H2
`
`H3
`
`H4
`
`Immunomodulatory effects
`Itching
`Swelling
`Erythema
`" Vascular permeability
`Pain
`Vasodilation
`Nasal congestion
`
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`Eye allergy
`
`H1 RECEPTOR
`H1 histamine receptors are located in the bronchi,
`central nervous system (CNS), arterial and intestinal
`smooth muscle and the heart. Stimulation of H1
`receptors is associated with effects such as inflam-
`mation, prostaglandin production, pain, headache,
`hypotension, tachycardia and bronchoconstriction.
`The H1 receptor is the only histamine receptor
`associated with itching. Studies have shown that
`H1 antagonism can prevent the cytokine release
`and ocular itching associated with allergic conjunc-
`tivitis. Further studies demonstrated that vascular
`permeability is controlled by the H1 receptor sub-
`type. H1 receptors are extensively involved in CNS
`and smooth muscles that underlie some of the side
`effects seen with oral antihistamines, such as som-
`nolence and cardiac side effects [2]. The signature
`sedative effect of first generation of oral antihist-
`amines, including compounds such as diphenhydr-
`amine and chlorpheniramine, was due to their
`ability to cross the blood–brain barrier and exert
`H1 blocking effects in the CNS [4].
`
`H2 RECEPTOR
`H2 receptors are located in the parietal cells of the
`gastric mucosa and are most well known for their
`role in gastric acid secretion. Members of a class of
`medications for gastric acid reflux disease, including
`cimetidine and famotidine, are H2 receptor inhibi-
`tors. H2 histamine receptors are also located in the
`heart, uterus, and CNS. When stimulated, H2 recep-
`tors are involved with cytokine production, an
`increase in vascular permeability, flushing, bron-
`chial smooth muscle relaxation, secretion of gastric
`acid and various inflammatory effects. The H2 recep-
`tor shares with the H1 receptor an involvement in
`vasodilation. A study [5] of stimulated vasodilation
`in the conjunctiva found this effect was prevented
`with prior administration of an H2 antagonist.
`
`H3 RECEPTOR
`The H3 histamine receptors are primarily found in
`neurons located in the CNS and peripheral nervous
`system, in the heart and in bronchioles. These recep-
`tors are located presynaptically, and their stimu-
`lation inhibits the release of histamine and other
`neurotransmitters, as well as enhances modulation
`of the blood–brain barrier. Stimulation of H3 recep-
`tors leads to a decrease in gastric acid production,
`bronchial relaxation,
`inhibition of sympathetic
`neurotransmission and control of vasoactive media-
`tors. Drugs that affect the H3 receptor are currently
`being studied for
`the treatment of
`insomnia,
`obesity, inflammatory diseases, schizophrenia and
`
`other disease states impacted by neurotransmitter
`release [6]. There are currently no H3 agonists or
`antagonists in clinical use.
`Animal models suggest the H3 receptor also has
`involvement in nasal congestion, and H3 blockade
`may provide relief of congestion symptoms. Com-
`bination H1 antagonism with chlorpheniramine
`and H3 antagonism with either chlobenpropit
`or thioperamide showed significant decongestive
`effects, although avoiding the common side effect
`of hypertension seen with most sympathomimetic
`decongestants [7]. Another study [8] combined fex-
`ofenadine, an H1 receptor antagonist, with a novel
`H3 blocking agent and found that superior sympto-
`matic relief was achieved when H3 receptors were
`also antagonized. Statistically significant relief of
`subjective rhinorrhea,
`itching and sneezing was
`greater with the addition of an oral H3 antagonist,
`and fexofenadine and an H3 blocker significantly
`lowered congestion symptom scores compared with
`placebo. These results support the notion that H3
`receptors are involved in sympathetic transmission
`and also suggest that oral H3 antagonists, in com-
`bination with H1-blocking agents, may be of use for
`the treatment of allergic rhinitis symptoms. These
`symptoms include nasal congestion, which is not
`relieved with present antihistamine-only treatment
`options.
`
`H4 RECEPTOR
`H4 receptors are found in leukocytes, mast cells and
`peripheral hematopoietic cells. The stimulation of
`H4 receptors leads to mast cell activation, eosinophil
`recruitment and differentiation of myelocytes and
`promyleocytes. The H1 receptor antagonists have
`little affinity for H4 receptors, but H3 antagonists,
`and some H2 antagonists, have some affinity for the
`H4 receptor. H4 receptors are involved in auto-
`immune reactions, allergies, and with the specific
`symptom of pruritus. Due to its proposed immuno-
`modulating effects, the H4 receptor is being inves-
`tigated as a potential target for antiallergy therapy,
`and experimental compounds that antagonize the
`H4 receptor are currently being examined as possible
`treatments for immune-related disease states such as
`asthma [9,10]. Antagonists at the H1 receptor are
`largely ineffective in asthma, but studies have
`suggested that blocking the H4 receptor may control
`asthmatic symptoms. One study [11] found that
`H4-receptor knockout mice had statistically signifi-
`cant decreases in cytokine release and airway
`inflammation than wild-type mice.
`The H4 receptor is also believed to be involved in
`itching, and in a murine model, H4-receptor knock-
`out mice given a dose of histamine or an H4-receptor
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`agonist exhibited fewer bouts of scratching com-
`pared with wild-type animals [12]. Following injec-
`tion of histamine or an H4 agonist, itching was
`significantly prevented in both groups by pretreat-
`ing with an experimental H4-receptor antagonist.
`No itch relief was seen, if mice were pretreated with
`H2-receptor or H3-receptor antagonists, and signifi-
`cantly less symptom relief was shown with diphen-
`hydramine than with the H4 antagonist.
`It is hypothesized that synergistic control and
`prevention of symptoms such as itching and inflam-
`mation related to allergic disease states can be
`achieved with combination H1/H4 receptor antagon-
`ism [4]. The study [12] in murine models with
`induced pruritus showed statistically significant
`decreases in scratching when the H1 antagonist
`diphenhydramine was administered concurrently
`with an H4 blocker, as compared with either agent
`alone, and scratching that did occur in H4-receptor
`knockout mice was eliminated by administering
`diphenhydramine.
`
`METHODS
`We searched the literature for studies regarding bind-
`ing affinities of antihistamines to the different his-
`tamine receptors. A comparison of 19-marketed
`antihistamines shows differences in receptor affinity
`and drug potency. A lower binding affinity value (Ki)
`corresponds to stronger binding affinity of the drug
`for the receptor. If the binding affinity for the recep-
`tor is strong, less of that drug is needed to achieve
`inhibition of that receptor [2]. The Ki values for
`each antihistamine, as determined by the studies
`examined, were compared to determine relative
`potency among the agents. Comparative potencies
`of marketed antihistamines for muscarinic receptor
`inhibition were also examined to determine the like-
`lihood of these agents to cause anticholinergic side
`effects. It should be emphasized that these binding
`affinities are from different studies so are not direct
`comparisons, but some general trends emerge.
`
`DIFFERENTIAL AFFINITIES FOR THE H1
`RECEPTOR
`For perspective, the binding affinity of histamine
`itself for the H1 receptor is 180 000 nM. Many of the
`antihistamine drugs evaluated have a much greater
`binding affinity for the H1 receptor than does his-
`tamine. Thioperamide had the lowest affinity for
`the H1 receptor, with a Ki value of 280 000 nM.
`Of the antihistamines compared, pyrilamine
`showed the highest affinity for the H1 receptor, with
`a Ki value of 0.8 nM. The first-generation drug
`(Ki¼ 12.5 nM),
`diphenhydramine is very potent
`
`Ophthalmic antihistamines and H1 H4 receptors Wade et al.
`
`but potency is variable among the second-generation
`compounds. Desloratadine and cetirizine showed
`the most affinity (Ki¼ 4 and 6.3 nM, respectively),
`followed by loratadine (Ki¼ 35 nM). Fexofena-
`dine had the lowest binding affinity of the second-
`generation antihistamines and of the H1 receptor
`antagonists in general, with a binding affinity value
`of 83 nM [2].
`Among those drugs most recently introduced as
`topical ophthalmic formulations in the United
`States (azelastine, epinastine, ketotifen, olopata-
`dine), potency is generally high, with olopatadine
`having the lowest binding affinity of the group
`(Ki¼ 31.6) [13]. Ketotifen and emedastine showed
`the greatest affinity among the topical antihist-
`amines, with binding affinity values of 1.3 nM for
`both drugs [2,14].
`
`DIFFERENTIAL AFFINITIES FOR THE H2
`RECEPTOR
`The dynamics of drug to H2 receptor binding may
`well be different from drug to H1 receptor inter-
`actions. When you compare H2 binding affinities
`with H1 binding affinities, drug affinities for the H2
`receptor are two to four orders of magnitude weaker
`than for the H1 receptor.
`As with the H1 receptor, there are substantial
`differences in the binding affinities of various com-
`pounds for the H2 receptor. Of the antihistamines
`compared, ranitidine showed the greatest affinity
`for the H2 receptor (Ki¼ 187 nM) [2]. The weakest
`binding affinity for the H2 receptor occurred with
`olopatadine (Ki¼ 100 000 nM) [13]. Of the various
`antihistamines compared, only diphenhydramine,
`azelastine, epinastine and ketotifen exhibited bind-
`ing affinities in the range of cimetidine, which is a
`well characterized H2-receptor antagonist [2].
`The binding affinity of a drug in comparison to
`histamine can predict the drug’s ability to compete
`for the receptor site and produce an antihistamine
`effect. Histamine’s affinity for the H2 receptor is
`18 350 nM. Two drugs, emedastine (Ki¼ 49 067 nM)
`nM) and olopatadine (Ki¼ 100 000 nM), appear to
`have lower binding affinities for the H2 receptor
`compared with histamine, suggesting that a very
`high concentration of either drug might be required
`simply to outcompete histamine for binding to the
`receptor [13,14]. The clinical significance of this is
`not known.
`
`DIFFERENTIAL AFFINITIES FOR THE H3
`AND H4 RECEPTORS
`The H3 and H4 share the most similarities to each
`other of all the histamine receptors [10]. Of the
`
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`Eye allergy
`
`compared antihistamines, the highest affinity for
`the H3 receptor was shown with thioperamide
`(Ki¼ 79 400 nM). Olopatadine exhibited the lowest
`affinity for the H3 receptor (Ki¼ 79 400 nM) [13].
`Limited data exist regarding binding affini-
`ties for the H4 receptor. Only five antihistamines
`were compared: ketotifen, pheniramine, ranitidine,
`cimetidine and thioperamide. Affinity for
`the
`receptor was greatest with thioperamide
`H4
`(Ki¼ 27 nM). Cimetidine and ranitidine exhibited
`relatively low affinity for H4 (Ki 10 000 nM) [2].
`More study of various drugs and their activity at the
`H4 receptor is needed to determine their utility as
`agonists or antagonists for this receptor and their
`place, if any, in the treatment of allergic and inflam-
`matory disease states.
`
`DIFFERENTIAL AFFINITIES FOR
`MUSCARINIC RECEPTORS
`Comparison of marketed antihistamines was
`examined for the M1 and M3 muscarinic receptor
`types as a percentage of the inhibition of intracellu-
`lar calcium mobilization via acetylcholine acti-
`vation of the receptor. Antihistamines were tested
`for anticholinergic activity. For the M1 receptor, the
`greatest anticholinergic activity was shown with
`desloratadine. The ideal antihistamine should have
`
`high antihistamine potency against the H1 receptor,
`combined with low antimuscarinic activity. See
`Fig. 1 [15].
`
`SELECTED OPHTHALMIC PREPARATIONS
`FOR THE TREATMENT OF ALLERGIC
`CONJUNCTIVITIS
`There are several topical options for treating allergic
`conjunctivitis; below we discuss a selection of
`ophthalmic antihistamines.
`
`KETOTIFEN
`Ketotifen is a strong H1 receptor antagonist and
`mast cell stabilizer with leukotriene inhibition. It
`is, as of this publication, the only antihistamine/
`mast cell stabilizer topical ophthalmic agent avail-
`able without a prescription in the United States
`(Alaway). It is available in a 0.025% formulation
`and administered twice daily. Ketotifen was found
`to be effective in prevention of itching, redness and
`other symptoms of allergic conjunctivitis compared
`with placebo [16]. A randomized, double-masked,
`placebo-controlled study [17] compared ketotifen
`fumarate and emedastine difumarate (an H1 recep-
`tor antagonist) and found they both statistically
`decreased the incidence of itching compared with
`
`Comparative pharmacology of marketed antihistamines
`
`Hydroxyzine
`
`Alcaftadine
`
`Epinastine
`
`Cetirizine
`
`Bepotastine
`
`Fexofenadine
`
`Olopatadine
`
`Ketotifen
`
`Azelastine
`
`Diphenhydramine
`
`Desloratadine
`
`Doxepin
`
`Increasing H1 antihistamine potency
`
`No
`activity
`
`Moderate
`potency and
`promiscuity
`
`Potent and
`promiscuous
`
`antimuscarinic activity
`
`Increasing
`
`FIGURE 1. Comparative pharmacology of marketed antihistamines. The ideal antihistamine should have high antihistamine
`potency against the H1 receptor, combined with low antimuscarinic activity. Note that the Y-axis on this chart displays drug
`potency and affinity for muscarinic receptor subtypes M1 through M5. The most promiscuous compounds displayed are
`Clarinex and Zaditor, which interact with all five muscarinic receptor subtypes. Adapted from [15].
`
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`placebo, but there was no significant difference
`between the two agents.
`
`OLOPATADINE
`Olopatadine is an H1-selective antagonist and mast
`cell stabilizing agent, available for ophthalmic use
`in two formulations: a 0.1%, twice-daily agent
`(Patanol manufactured by Alcon Laboratories,
`Inc, Fort Worth, TX) and a 0.2%, once-daily agent
`(Pataday manufactured by Alcon Laboratories, Inc,
`Fort Worth, TX). The 0.1% formulation is approved
`for the treatment of allergic conjunctivitis symp-
`toms, making it unique among the other H1
`blocker/mast cell stabilizer ophthalmic agents, all
`of which are approved for ocular itching only. In
`two three-visit comparative studies [18,19], olopa-
`tadine was found to be significantly superior to
`both nedocromil and ketotifen in the relief of
`ocular itching. Olopatadine was also preferred by
`study participants over either alternative and rated
`significantly more comfortable in both cases. An
`intranasal formulation of olopatadine (Patanase
`manufactured by Alcon Laboratories, Inc, Fort
`Worth, TX) is also available for the treatment of
`allergic rhinitis.
`
`AZELASTINE
`Azelastine is a selective H1-receptor antagonist that
`also exhibits H2-blocking properties. Azelastine has
`also been shown to block the release of histamine
`from mast cells in response to stimuli and the for-
`mation of leukotrienes. It is approved for the treat-
`ment of ocular itching and has been shown to be
`efficacious for up to 8 h, with twice-daily use recom-
`mended. It has a pH of 5.0–6.5 and a relative com-
`mon incidence of ocular irritation, with common
`adverse events including a burning and stinging
`sensation in the eye after administration. Like
`olopatadine, it is also available in an intranasal
`formulation [20,21].
`
`EPINASTINE
`Epinastine is an antihistamine with a high affinity
`for the H1 receptor and also exhibits mast cell
`stabilizing properties and H2 antagonism. When
`administered in the eye, epinastine has been
`shown to significantly decrease itching, injection,
`swelling and tearing compared with placebo [22].
`It has a duration of action of 8 h or longer and is
`used twice daily [21,22]. Epinastine is associated
`with few adverse events, including burning and
`infection, and is well tolerated for use up to 8 weeks
`[21].
`
`Ophthalmic antihistamines and H1 H4 receptors Wade et al.
`
`BEPOTASTINE
`Bepotastine is an H1-selective antagonist with mast
`cell stabilizing and eosinophil modulating pro-
`perties. It was approved as a 1.5% ophthalmic
`solution in the United States in 2009 for the treat-
`ment of itching associated with allergic conjuncti-
`vitis. Bepotastine is superior to placebo in the
`prevention of itching and ocular tearing when
`administered 16 h prior to CAC, but in the same
`time frame showed little utility in the prevention of
`conjunctival redness [23&]. Bepotastine has been
`shown to be effective at relieving ocular itching as
`soon as 3 min after administration, and for up to 8 h
`following [24]. In guinea pig models of conjuncti-
`vitis, bepotastine besilate 1.0% inhibited vascular
`permeability due to histamine significantly more
`potently than olopatadine 0.1%. Bepotastine was
`also shown to inhibit eosinophil infiltration into
`the conjunctiva as well as ketotifen [25].
`
`ALCAFTADINE
`Alcaftadine, a tricyclic piperidine aldehyde, was
`approved in 2010 for the prevention of itching
`associated with allergic conjunctivitis. It is available
`by prescription in a 0.25% ophthalmic solution and
`is administered once daily. Ophthalmic alcaftadine
`shows similar pharmacokinetic activity to oral
`administration. Alcaftadine is likely metabolized
`primarily by cytosolic enzymes via aldehyde oxi-
`dation to its acid metabolite; it is thought that
`cytochrome p450 enzymes play a minor role in this
`metabolism [26&]. Alcaftadine exhibits antagonistic
`activity at H1, H2 and, with lower affinity, at H4
`receptors, making it unique among the antihist-
`amine/mast cell stabilizer ophthalmic preparations.
`Additionally, alcaftadine prevents the recruitment
`of eosinophils and inhibits mast cell degranulation
`[1&]. In a murine model, alcaftadine treatment
`resulted in less eosinophil infiltration into the con-
`junctiva when compared with olopatadine and
`placebo [27&]. Alcaftadine was shown to be statisti-
`cally and clinically significantly superior to placebo
`in the prevention of itching at 15 min and 16 h after
`treatment. It was also superior to placebo in pre-
`vention of ocular redness; however, this result was
`statistically but not clinically significant [28&]. A
`head-to-head study [29&] comparing three concen-
`trations of alcaftadine to placebo and to olopatadine
`found alcaftadine to have a faster onset of action
`and superior itching prevention after 16 h compared
`with olopatadine and placebo.
`
`CONCLUSION
`There are four known types of histamine receptors
`(H1–H4), and each receptor varies in physiological
`
`515
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`www.co-allergy.com
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`Eye allergy
`
`effect. Antihistamines vary in their affinity to bind
`to each of these. Data comparing the affinity of
`marketed antihistamines to these receptors may
`be interpreted to establish their relative potency
`for each receptor type. The most recently introduced
`topical anithistamine for the treatment of allergic
`conjunctivitis, alcaftadine, is novel in that it is the
`first ophthalmic drug to target both the H1 and H4
`receptors. Further research into the activity of var-
`ious antihistamines and their activity at the H4
`receptor is needed to determine what future place
`this receptor may have in the treatment of allergic
`and inflammatory disease states.
`
`Acknowledgements
`None.
`
`Conflicts of interest
`There are no conflicts of interest.
`
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