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Histamine and antihistamines
PHARMACOLOGY
Histamine and antihistamines
Learning objectives After reading this article, you should be able to: C describe the role of histamine in health and disease C describe the four classes of histamine receptors C understand the current and future clinical application of antihistamines
Amr M Mahdy Nigel R Webster
Abstract Histamine is one of the most extensively studied biological amines in medicine. It stimulates smooth muscle contraction and gastric acid secretion, increases vascular permeability, functions as a neurotransmitter, and plays various roles in immunomodulation, allergy, inflammation, haematopoiesis and cell proliferation. Histamine exerts its effects through four receptors, designated H1eH4. H1 and H2 receptors are widely distributed, H3 receptors are mainly presynaptic, and H4 receptors are mainly haematopoietic. H1 antihistamines are classified as first- and second-generation compounds. First-generation compounds lack specificity and cross the bloodebrain barrier causing sedation. Second-generation compounds are less sedating and highly specific. H1 antihistamines have well-documented anti-allergic and anti-inflammatory effects and are well established in the treatment of a variety of allergic disorders. First-generation antihistamines are also used in the treatment of vestibular disorders and can be used as sedatives, sleeping aids and anti-emetics. H2 antihistamines are widely used in the treatment of gastric acid-related disorders; however, proton pump inhibitors are becoming the drugs of first choice in some of these disorders. H3 antihistamines are expected to be of potential value in the treatment of some cognitive disorder. H4 antihistamines could be of potential therapeutic benefit in the management of various immune and inflammatory disorders.
histamine is involved in the regulation of sleep and wakefulness, cognition, memory, and energy and endocrine homeostasis. It also modulates the release of several neurotransmitters through presynaptic receptors located on histaminergic and nonhistaminergic neurones of the central and peripheral nervous system. Histamine also plays a pivotal role in the pathogenesis of allergic inflammation. In response to an antigen, reaginic antibodies of the immunoglobulin (Ig)E type are generated. These antibodies bind to specific receptors expressed on the surface of mast cells and basophils. The binding triggers a complex chain of intracellular reactions leading to exocytosis and release of histamine along with tryptase, leukotrienes and prostaglandins as well as other mediators. Alternatively, histamine can be directly displaced and released from its storage granules upon exposure to certain organic bases, including drugs such as morphine and tubocurarine. Subsequent binding of histamine to central and peripheral histamine receptors leads to immediate, concentration-dependent smooth muscle contraction in the respiratory and gastrointestinal tracts, vasodilatation and sensory nerve stimulation. These actions of histamine manifest clinically as erythema, pruritus, nasal congestion, flushing, headache, hypotension, tachycardia and bronchoconstriction. Moreover, in addition to its role in the early allergic response, 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. Histamine is formed by decarboxylation of the amino acid Lhistidine in a reaction catalysed by the enzyme histidine decarboxylase (HDC). Mast cells, basophils, enterochromaffinlike cells of the gastric mucosa, and histaminergic neurones synthesize considerable amounts of histamine and store the mediator in special storage granules inside the cells. Upon appropriate stimulation, these cells can rapidly release relatively large amounts of histamine and thereby efficiently activate suitable effector mechanisms. Apart from these histaminestoring cell types, many other cells including epithelial cells and lymphocytes can express HDC and synthesize histamine. However, in these cells, histamine is immediately released and is not stored. In humans, histamine is metabolized by histamine N-methyltransferase to N-methylhistamine, which can be further metabolized to N-methyl-imidazole acetic acid by the enzyme monoamine oxidase. Alternatively, histamine can be metabolized by diamine oxidase (DAO) to imidazole acetic acid, which can be further conjugated to form imidazole acetic acid ribose. In the gut wall, DAO is responsible for metabolizing dietary histamine present in considerable amounts in certain foods, preventing its
Keywords Antihistamines; histamine; histamine receptors Royal College of Anaesthetists CPD matrix: 1A02
Histamine, 2-(4-imidazole)-ethylamine, was chemically synthesized for the first time by Windaus and Vogt in 1907; however, it was not until 1910 that Henry Dale and Patrick Laidlaw characterized its biological effects. Since that date histamine has become one of the most extensively studied biological amines in medicine. In addition to its well-known three functions (smooth muscle contraction, increased vascular permeability and stimulation of gastric acid secretion), histamine plays various roles in immunomodulation, inflammation, regulation of cell proliferation and differentiation, haematopoiesis, embryonic development, regeneration and wound healing. Moreover, as a neurotransmitter,
Amr M Mahdy FRCA MD is a Consultant Anaesthetist at Aberdeen Royal Infirmary and an Honorary Senior Lecturer at the University of Aberdeen, UK. Conflict of interest: none declared. Nigel R Webster FRCP FRCS is a Professor of Anaesthesia and Intensive Care at the University of Aberdeen, UK. Conflict of interest: none declared.
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PHARMACOLOGY
uptake into the circulation. However, the DAO pathway is not active in the central nervous system.
The histamine H3 receptor is found mainly in the central nervous system (basal ganglia, hippocampus and cortical areas), but can also be found in the peripheral nervous system, airways, the cardiovascular system, and the gastrointestinal tract. Acting through presynaptic H3 receptor, histamine regulates its own release as well as the release of other neurotransmitters such as noradrenaline, dopamine, serotonin, acetylcholine, and gammaamino-butyric acid. In the lower airways, H3 receptors are located on postganglionic cholinergic nerves and defend against excess bronchoconstriction and in the upper airways, histamine may play a role in nasal congestion through its activity at H3 receptors. The H4 receptor has been detected in bone marrow, peripheral blood, spleen, thymus, lung, gastrointestinal tract, liver, peripheral nerves, and central neurones. Nevertheless, cells that clearly express functional H4 receptors are mainly haematopoietic and include: mast cells, eosinophils, basophils, dendritic cells, and T cells. H4 receptor activation induces calcium mobilization in mast cells and mediates mast cells migration towards histamine. Moreover the receptor plays a significant role in regulating dendritic and T-cell function. In general terms, the four histamine receptors can be described as heptahelical G-protein coupled receptors. They transduce extracellular signals through various G proteins, which function as mediators between the cell surface receptors and the intracellular second messenger systems. Histamine receptors exist in an equilibrium between two conformational states (Figure 1), active (R*) or inactive (R).
Histamine receptors Histamine exerts its diverse biologic effects through four types of receptors; H1, H2, H3 and H4 receptors (Table 1). Additionally, low-affinity intracellular non-H1, -H2, -H3, or -H4 receptors, have been recently described in cell nuclei and microsomes, although biologic functions at these receptors is still somewhat unclear. The H1 receptor is widely distributed throughout the body, with well-documented expression in the CNS, smooth muscle, sensory nerves, heart, adrenal medulla, and immune, endothelial, and epithelial cells. The H1 receptor mediates most of the postsynaptic effects of histamine within the central nervous system. Moreover, through its activity at H1 receptors, histamine stimulates smooth muscle contraction in the respiratory and gastrointestinal tract, stimulates sensory nerves leading to pruritus and sneezing, and increase vascular permeability leading to oedema. Simultaneous activation of H1 and H2 receptor can also result in hypotension, tachycardia, flushing, and headache. The H2 receptor is also widely expressed and can be found in gastric mucosal cells, heart, CNS, immune cells, and smooth muscles of the airway, vasculature, and uterus. H2 receptor activation stimulates hydrochloric acid secretion from the acidsecreting parietal cells of the gastric mucosa, leads to smooth muscle relaxation in the vasculature and airways, increases cardiac rate and contractility, and mediates some of the immunomodulatory effects of histamine.
Histamine receptor subtypes along with their selective agonists, inverse agonists/antagonists, G-protein coupling and signal transduction Receptor subtype
H1
H2
H3
H4
G-protein coupling Signal transduction
Gq/11
Gs
Gi/o
Gi/o
Phospholipase C activation / [ IP3 and DAG / [ Intracellular Ca and protein kinase C activation C Phospholipase A2 activation / [ Arachidonic acid C NOS activation C Phospholipase D activation
Adenylate cyclase activation / [ cAMP / Protein kinase A activation
C
C
Selective agonists
Histaprodifen
Amthamine Dimaprit Impromidine
Antagonists/ inverse agonists (examples)
Chlorphenamine Promethazine Loratidine Fexofenidine
Cimetidine Ranitidine Famotidine Nizatidine
Adenylate cyclase inhibi- C Adenylate cyclase inhibition / tion / Y cAMP Y cAMP C MAPK pathway activation C MAPK pathway activation C Phospholipase A2 activation / [ Arachidonic acid C Inhibition of Na/H exchanger C Y Intracellular Ca Clobenopropit (partial Alpha-Methyl-histamine agonist) Imetit Imetit Immepip Immepip 4-Methylhistamine Thioperamide JNJ-7777120 Pitolisant (ABT-288) VUF-6002 MK-0249 JNJ-17216498 C
IP3, inositol triphosphate; DAG, diacylglycerol; NOS, nitric oxide synthase; cAMP, cyclic adenosine monophosphate; MAPK, mitogen-activated protein kinase.
Table 1
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PHARMACOLOGY
The two-state model of histamine receptors a
R
R
R*
c Inverse agonist
R
Agonist
b
Resting state
R*
Agonist
d True antagonist
R*
R
R*
(a) In the resting state, a balance exists between the active receptors R* and the inactive receptors R; (b) Agonists bind to the active state shifting the equilibrium towards R*; (c) Inverse agonists bind to the inactive state shifting the equilibrium towards R; (d) True antagonists bind to both active and inactive receptors interfering with agonist binding but with no effect on R/R* equilibrium. Figure 1
Moreover, they all have constitutive activity, which is defined as the ability to trigger downstream events even in the absence of ligand binding (receptors changing from R to R* in the absence of a ligand). Based on this two-state model, ligands at the histamine receptors can be classified into agonists (bind to the active state and shift the equilibrium towards R*), true antagonists (bind to both active and inactive state interfering with agonist binding but with no effect on equilibrium or intrinsic receptor activity), and inverse agonists (bind to the inactive state shifting the equilibrium towards R, and reduce the intrinsic activity of the receptor in the absence of an agonist). Most currently known antihistamines have been reclassified as inverse agonists and the term histamine antagonists is only reserved for those compounds that function as true antagonists. In the following paragraphs the term antihistamines is used to describe drugs with inverse agonist or antagonist activity at a given histamine receptor.
As mentioned earlier, the vast majority of H1 antihistamines exert their antihistaminic action by acting as inverse agonists at the H1 receptors; binding to and stabilizing the inactive state of the H1 receptor and reducing the intrinsic activity of the receptor even in the absence of an agonist. Based on their pharmacological structure, H1 antihistamines are traditionally classified into six groups: ethanolamines, ethylene diamines, alkylamines, piperazines, piperidines, and phenothiazines. This classification is, however, of limited clinical relevance, and currently H1 antihistamines are classified as ‘first generation’, also known as ‘sedating antihistamines’, and ‘second generation’, which are relatively non-sedating (Table 2). The terms ‘thirdgeneration’ and ‘new-generation’ antihistamines are sometimes used to describe some newly produced antihistamines that are selective isomers or active metabolites of older second-generation antihistamines. However, there is currently no consensus on such terminology, and for the purpose of this review these newer agents will still be considered as second-generation antihistamines. First-generation H1 antihistamines such as alimemazine, chlorphenamine, clemastine, cyproheptadine, hydroxyzine, and promethazine are non-selective in binding to the H1 receptor. Most of these drugs have weak antimuscarinic anticholinergic effects, some have alpha-adrenergic blocking effects (promethazine), and others can inhibit both histamine and 5hydroxytryptamine activity (cyproheptadine). Owing to their lipophilicity, relatively low molecular weight, and lack of recognition by the P-glycoprotein efflux pump, first-generation H1 antihistamines readily penetrate the non-fenestrated capillaries of the central nervous system (CNS; bloodebrain barrier)
H1 antihistamines In 1937, the first H1 antihistamine (thymo-ethyl-diethylamine) was synthesized. However, because of weak activity and high toxicity, this compound was not used in clinical practice. Clinically useful H1 antihistamines such as phenbenzamine, pyrilamine, and diphenhydramine were introduced in the 1940s. Currently, H1 antihistamines constitute the second most commonly used class of medications after antibiotics, with more than 40 varieties of H1 antihistamines used in clinical practice worldwide.
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PHARMACOLOGY
Comparison between first- and second-generation H1 antihistamines
Receptor selectivity
Central H1 occupation Examples
Clinical uses
Side-effects
First generation
Second generation
Inverse agonists at H1 receptors Weak antimuscarinic a-Anti-adrenergic (promethazine) Anti-serotonergic (cyproheptadine) High occupancy Alimemazine Chlorphenamine Clemastine Cyproheptadine Hydroxyzine Promethazine Cyclizine Cinnarizine Allergic rhinitis Atopic dermatitis Acute and chronic urticaria Insect bites and stings Anaphylaxis (intravenous chlorphenamine) URT infection (no evidence) Insomnia Sedative premedication (promethazine) Vertigo and motion sickness (cinnarizine) Treatment/prevention of PONV (cyclizine) CNS depression (somnolence, impaired cognitive and psychomotor performance); other CNS effects (seizures, dyskinesia, dystonia, hallucinations) Anticholinergic effects (dry mouth, blurred vision, urine retention) Drugs of abuse Drugs of suicide and infants’ homicide Weight gain (cyproheptadine)
Highly selective for H1 receptors
0e30% occupancy Acrivastine Bilastine Cetirizine Levocetirizine (isomer of cetirizine) Loratadine Desloratadine (metabolite of loratadine) Mizolastine Fexofenadine (metabolite of terfenadine) Allergic rhinitis Atopic dermatitis Acute and chronic urticaria Insect bites and stings Seasonal asthma with allergic rhinitis URT infection (no evidence)
Minimal or no CNS depression Minimal or no anticholinergic effects Polymorphic ventricular tachycardias with torsade de pointes and ventricular fibrillation (astemizole and terfenadine; both not in clinical use)
CNS, central nervous system; URT, upper respiratory tract; PONV, postoperative nausea and vomiting.
Table 2
and bind to central H1 receptors, interfering with the actions of histamine on these receptors. Second-generation H1 antihistamines such as cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine and mizolastine have significantly less affinity for muscarinic cholinergic, alpha-adrenergic and 5-hydroxytryptaminergic receptors and penetrate poorly into the CNS because of their low lipid solubility, relatively high molecular weight and affinity for the Pglycoprotein efflux pump. Their propensity to occupy central nervous system H1 receptors varies from none for fexofenadine to 30% for cetirizine. H1 antihistamines, both first and second generation, have well-documented anti-allergic and anti-inflammatory effects. They exert these effects through their inverse agonist activity at peripheral H1 receptors and through other non-receptormediated mechanisms (e.g. inhibition of mast cell and basophil histamine release and inhibition of inflammatory cell activation). They are currently well established as first- or second-line treatments for a variety of allergic disorders.
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All H1 antihistamines are of potential value in the management of seasonal (intermittent) and perennial (persistent) allergic rhinitis in which they relieve nasal and conjunctival itching, sneezing and rhinorrhoea and improve the quality of life. They are also useful in the treatment of acute and chronic urticaria as they provide symptomatic relief of itching and reduce the number, size and duration of individual hives. However, the evidence for using first-generation drugs in the treatment of these disorders remains surprisingly small by current standards and most available evidence is derived from large randomized, controlled trials using second-generation drugs. Moreover, first-generation H1 antihistamines have an unsatisfactory benefit-to-risk ratio owing to their sedating effects, and although generally less expensive than second-generation drugs, when costs attributed to their adverse effects are considered, the difference may be less than expected. Second-generation H1 antihistamines should, therefore, be the preferred choice in the treatment of these disorders because of their lack of sedative, cognitive and psychomotor performanceimpairing and antimuscarinic anticholinergic adverse effects.
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PHARMACOLOGY
H1 antihistamines are also used in the management of atopic dermatitis both for relief of itching and for their glucocorticoidsparing effects; however, the evidence in support of their efficacy is considerably weaker than it is in allergic rhinitis and urticaria. They are also administered to treat local allergic reactions to insect bites and stings. H1 antihistamines, usually in combination with a decongestant, are widely used to relieve symptoms in upper respiratory tract infections, otitis media and sinusitis. However, the published evidence does not support this practice and it is currently thought that the beneficial effects sometimes reported with firstgeneration drugs are due at least in part to their sedating and antimuscarinic effects. Similarly, current evidence does not support the use of H1 antihistamines in persistent asthma. However, in patients with allergic rhinitis and asthma, the use of second-generation H1 antihistamines has been shown to relieve co-existing mild seasonal asthma symptoms, reduce beta-2 adrenergic agonist requirements and improve pulmonary function. First-generation H1 antihistamines such as chlorphenamine and promethazine are used intravenously for the management of anaphylaxis when hypotension is unresponsive to epinephrine. Since most second-generation H1 antihistamines have low aqueous solubility, they are not available in formulations for injection and hence cannot be used in such circumstances. Owing to their ability to cross the bloodebrain barrier, firstgeneration H1 antihistamines such as promethazine are used as non-prescription sleeping aids; promethazine is commonly used as a sedative premedication in children; and cinnarizine, promethazine and cyclizine, are used for the prevention and treatment of symptoms of vertigo and motion sickness. Moreover, cyclizine has a well-established role in the prevention and management of postoperative nausea and vomiting. The anti-emetic effect of these drugs stems from their antimuscarinic properties and from their ability to block the histaminergic signal from the vestibular nucleus to the vomiting centre in the medulla. A wide variety of adverse effects has been attributed to firstgeneration H1 antihistamines. They readily penetrate the blood ebrain barrier and hence have the potential to cause CNS depression, which usually manifests as somnolence and impaired cognitive and psychomotor performance. Their use can also lead to a variety of other adverse CNS effects, including seizures, dyskinesia, dystonia and hallucinations. Firstgeneration H1 antihistamines have also been associated with fatalities in accidental or intentional overdose, and are potential agents of suicide and of infants’ homicide. Moreover, some firstgeneration H1 antihistamines are drugs of abuse leading to euphoria and hallucinations. First-generation H1 antihistamines commonly cause antimuscarinic anticholinergic effects such as dry mouth, blurred vision and dysfunctional urine voiding. Gastrointestinal upset, jaundice and pancytopenias have also been reported. Cyproheptadine causes appetite stimulation and inappropriate weight gain secondary to anti-serotonin effects. Second-generation H1 antihistamines are considerably less likely than first-generation drugs to cause adverse effects. In manufacturers’ recommended doses, the second-generation H1 antihistamines impair CNS function significantly less than the first-generation H1 antihistamines. Moreover, they lack any anticholinergic antimuscarinic effects. There are occasional
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reports of fixed-drug eruptions, exacerbations of existing urticaria and hepatitis after cetirizine or loratadine ingestion. Two early second-generation H1 antihistamines, astemizole and terfenadine, which are no longer approved, block the rapid component of delayed rectifier potassium current (IKr). As a result, these two agents potentially prolong the QT interval and may lead to cardiac arrhythmias, including polymorphic ventricular tachycardias with torsade de pointes and ventricular fibrillation. New second-generation H1 antihistamines such as cetirizine, desloratadine, fexofenadine and loratadine have 1:1000 of the potency in blocking the IKr current and are free of potential cardiac toxicity in therapeutic and supra-therapeutic doses. The weight of evidence to date suggests that the potential of second-generation H1 antihistamines to cause ventricular arrhythmias is not a class effect.
H2 antihistamines In the 1960s, it became clear that ‘traditional antihistamines’ do not antagonize the stimulatory effect of histamine on gastric acid secretion, which lead to the assumption that histamine mediates its effect through two receptor subtypes designated H1 and H2 receptors. This hypothesis became generally accepted and the search for H2-specific antihistamines soon began. In 1969, burimamide, the first H2 antihistamine was discovered; however it was insufficiently potent for oral administration. Further modification of burimamide led to the development of metiamide, which was an effective agent; however, it was not suitable for clinical practice because of its bone marrow toxicity and nephrotoxicity. Further investigations into the activity and toxicity of similar compounds led to the discovery of cimetidine, which was the first clinically useful H2 antihistamine. This was followed by ranitidine, famotidine and nizatidine. Like H1 antihistamines, H2 antihistamines are inverse agonists and not true H2 antagonists, as was previously thought. They exert their antihistaminic effects by binding to, and stabilizing, the inactive state of the H2 receptor. Moreover, in the absence of histamine, these drugs can inhibit the constitutive activity of H2 receptors. H2 antihistamines inhibit the chronotropic, inotropic and delayed vasodilatory effects of histamine, and, of particular therapeutic importance, suppress basal and stimulated acid secretion by parietal cells. They accomplish the latter effect through their inverse agonist activity at the H2 receptors of the parietal cells, thus opposing the effects of histamine released by the enterochromaffin-like cells of the stomach. Moreover, these compounds attenuate the stimulatory effects of gastrin and acetylcholine on gastric acid production. The four H2 antihistamines are currently available over the counter in relatively low doses, and have become extremely popular in relieving the symptoms of gastro-oesophageal reflux disease (heart burn). As prescription medications, H2 antihistamines alone are not generally effective for more severe grades of gastrooesophageal reflux disease; however, they are still recommended and used widely for patients with mild or infrequent symptoms, and also, in combination with proton pump inhibitors for patients with persistent nocturnal symptoms. They are also used in the treatment of functional dyspepsia, but caution should be exerted as the regular use of these medications in uninvestigated dyspepsia can mask the symptoms of gastric malignancy in elderly patients.
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PHARMACOLOGY
serotonin, norepinephrine and gamma-amino-butyric acid. These effects could be of potential benefit in the treatment of sleep disorders, attention-deficit hyperactivity disorder, dementias, schizophrenia, and Alzheimer’s disease. Moreover, the peripheral actions of H3 antihistamine might prove to be of value in relieving nasal congestion in patients with allergic rhinitis. One of the most advanced H3 antihistamines in clinical development is the nonimidazole-based inverse agonist pitolisant (formerly known as tripolisant; BF2.649). Pitolisant has been granted orphan drug status by the European Medicine agency for the treatment of excessive diurnal sleepiness in patients with narcolepsy, Parkinson’s disease, and obstructive sleep apnoea/ hypopnoea. Several H3 antihistamine compounds are still undergoing phase I and phase II clinical trials. Compounds with an agonist activity at the H3 receptor are also being developed. These compounds can increase histamine and dopamine release and might be useful in the management of insomnia, migraine and schizophrenia.
H2 antihistamines can also be used to promote healing of nonsteroidal anti-inflammatory drug-associated ulcers, and have been used in high doses in ZollingereEllison syndrome; however, proton pump inhibitors are currently the first option in treating such conditions. In Helicobacter pylori-induced ulcers, maintenance treatment with low-dose H2 antihistamines has largely been replaced by eradication regimens involving the use of proton pump inhibitors, clarithromycin and either amoxicillin or metronidazole. These eradication regimens are usually effective in healing ulcers caused by H. pylori and treatment is seldom required for more than 4 weeks. However, in high-risk patients (e.g. those with a history of complications, frequent recurrences, ulcers testing negative for H. pylori, refractory giant ulcers, or severely fibrosed ulcers), maintenance therapy with H2 blockers or proton pump inhibitors is still indicated. H2 antihistamines are also used prophylactically to reduce the incidence of stress-related gastrointestinal bleeding (stressinduced ulcers) in intensive care patients, to reduce the frequency of bleeding from gastroduodenal erosions in hepatic coma, and to reduce the risk of acid aspiration in obstetric patients. They are also sometimes administered as a premedication before elective surgery to reduce the risk of acid aspiration; however, there is currently no evidence to support the latter practice. H2 antihistamines can also be used, off label, in combination with an H1 antihistamine in patients with acute and chronic urticaria that is refractory to treatment with an H1 antihistamine alone. Moreover, they can also be administered concomitantly with an H1 antihistamine in patients with anaphylaxis whose hypotension is unresponsive to epinephrine. In the latter case, H1 antihistamine should be given first, as rapid intravenous administration of cimetidine or ranitidine alone may exacerbate the hypotension and induce cardiac dysrhythmias. H2 antihistamines have a good safety record and are generally well tolerated. Side-effects include diarrhoea and gastrointestinal disturbances, altered liver function tests, headache, dizziness, rash and tiredness. Rare side-effects include acute pancreatitis, bradycardia, AV block, confusion, depression and hallucinations, particularly in the elderly. Hypersensitivity reactions, including fever, arthralgia, myalgia and anaphylaxis, and blood disorders, including agranulocytosis, leucopenia, pancytopenia and thrombocytopenia, have also been reported. Additionally, gynaecomastia, loss of libido and impotence have been reported in patients receiving cimetidine. Cimetidine is also a well-known inhibitor of the cytochrome P450 enzymes and therefore has the capacity to reduce the metabolism of drugs that are metabolized by these enzymes if given concomitantly. This is particularly relevant in patients receiving warfarin, phenytoin and theophylline, and hence cimetidine should be avoided in this group of patients.
H4 antihistamines The H4 receptor is the newest member of the histamine receptor family and, in contrast to other histamine receptors, it has a distinct expression profile on mast cells, eosinophils, dendritic cells and T lymphocytes. The H4 receptor plays a significant role in modulating a range of physiological functions of immune cells, including chemotaxis, cytokine release and adhesion molecule expression. Moreover, the use of H4 antihistamines in animal models of colitis, asthma and pruritus has already produced some promising results. It is therefore hoped that H4 antihistamines will be of therapeutic benefit in the management of various immune and inflammatory disorders in the future. Moreover, some recent evidence supports a novel role of the histamine H4 receptor in cancer progression representing a promising molecular target and avenue for cancer drug development. Alcaftadine is a new antihistamine with combined antagonist activity at histamine H1, H2, and H4 receptors. It significantly reduces itching, eosinophil recruitment and redness after exposure to an allergen. Alcaftadine was recently approved by the FDA for the prevention of itching associated with allergic conjunctivitis. A FURTHER READING Bernstein JA. Antihistamines. In: Grammer Leslie C, Greenberger Paul A, eds. Patterson’s allergic diseases. 7th edn. Lippincott Williams and Wilkins, 2009; 561e73. British Medical Association and the Royal Pharmaceutical Society of Great Britain. British national formulary. London: BMJ Publishing Group & RPS Publishing, 2014. Golightly LK, Greos LS. Second-generation antihistamines: actions and efficacy in the management of allergic disorders. Drugs 2005; 65: 341e84. Schwartz JC. The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol 2011; 163: 713e21. Simons FER. Advances in H1-antihistamines. N Engl J Med 2004; 351: 2203e18. Zampeli E, Tiligada E. The role of histamine H4 receptor in immune and inflammatory disorders. Br J Pharmacol 2009; 157: 24e33.
H3 antihistamines The successful cloning and functional expression of the histamine H3 receptor in the late 1990s facilitated the efforts of several pharmaceutical companies in developing a host of potential drugs that can therapeutically modulate the function of this receptor. In animal models, H3 antihistamines counteract the effects of histamine on presynaptic H3 receptors, and enhance the release of several neurotransmitters including histamine, dopamine,
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Histamine and antihistamines
Learning objectives After reading this article, you should be able to: C describe the role of histamine in health and disease C describe the four classes of histamine receptors C understand the current and future clinical application of antihistamines
Amr M Mahdy Nigel R Webster
Abstract Histamine is one of the most extensively studied biological amines in medicine. It stimulates smooth muscle contraction and gastric acid secretion, increases vascular permeability, functions as a neurotransmitter, and plays various roles in immunomodulation, allergy, inflammation, haematopoiesis and cell proliferation. Histamine exerts its effects through four receptors, designated H1eH4. H1 and H2 receptors are widely distributed, H3 receptors are mainly presynaptic, and H4 receptors are mainly haematopoietic. H1 antihistamines are classified as first- and second-generation compounds. First-generation compounds lack specificity and cross the bloodebrain barrier causing sedation. Second-generation compounds are less sedating and highly specific. H1 antihistamines have well-documented anti-allergic and anti-inflammatory effects and are well established in the treatment of a variety of allergic disorders. First-generation antihistamines are also used in the treatment of vestibular disorders and can be used as sedatives, sleeping aids and anti-emetics. H2 antihistamines are widely used in the treatment of gastric acid-related disorders; however, proton pump inhibitors are becoming the drugs of first choice in some of these disorders. H3 antihistamines are expected to be of potential value in the treatment of some cognitive disorder. H4 antihistamines could be of potential therapeutic benefit in the management of various immune and inflammatory disorders.
histamine is involved in the regulation of sleep and wakefulness, cognition, memory, and energy and endocrine homeostasis. It also modulates the release of several neurotransmitters through presynaptic receptors located on histaminergic and nonhistaminergic neurones of the central and peripheral nervous system. Histamine also plays a pivotal role in the pathogenesis of allergic inflammation. In response to an antigen, reaginic antibodies of the immunoglobulin (Ig)E type are generated. These antibodies bind to specific receptors expressed on the surface of mast cells and basophils. The binding triggers a complex chain of intracellular reactions leading to exocytosis and release of histamine along with tryptase, leukotrienes and prostaglandins as well as other mediators. Alternatively, histamine can be directly displaced and released from its storage granules upon exposure to certain organic bases, including drugs such as morphine and tubocurarine. Subsequent binding of histamine to central and peripheral histamine receptors leads to immediate, concentration-dependent smooth muscle contraction in the respiratory and gastrointestinal tracts, vasodilatation and sensory nerve stimulation. These actions of histamine manifest clinically as erythema, pruritus, nasal congestion, flushing, headache, hypotension, tachycardia and bronchoconstriction. Moreover, in addition to its role in the early allergic response, 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. Histamine is formed by decarboxylation of the amino acid Lhistidine in a reaction catalysed by the enzyme histidine decarboxylase (HDC). Mast cells, basophils, enterochromaffinlike cells of the gastric mucosa, and histaminergic neurones synthesize considerable amounts of histamine and store the mediator in special storage granules inside the cells. Upon appropriate stimulation, these cells can rapidly release relatively large amounts of histamine and thereby efficiently activate suitable effector mechanisms. Apart from these histaminestoring cell types, many other cells including epithelial cells and lymphocytes can express HDC and synthesize histamine. However, in these cells, histamine is immediately released and is not stored. In humans, histamine is metabolized by histamine N-methyltransferase to N-methylhistamine, which can be further metabolized to N-methyl-imidazole acetic acid by the enzyme monoamine oxidase. Alternatively, histamine can be metabolized by diamine oxidase (DAO) to imidazole acetic acid, which can be further conjugated to form imidazole acetic acid ribose. In the gut wall, DAO is responsible for metabolizing dietary histamine present in considerable amounts in certain foods, preventing its
Keywords Antihistamines; histamine; histamine receptors Royal College of Anaesthetists CPD matrix: 1A02
Histamine, 2-(4-imidazole)-ethylamine, was chemically synthesized for the first time by Windaus and Vogt in 1907; however, it was not until 1910 that Henry Dale and Patrick Laidlaw characterized its biological effects. Since that date histamine has become one of the most extensively studied biological amines in medicine. In addition to its well-known three functions (smooth muscle contraction, increased vascular permeability and stimulation of gastric acid secretion), histamine plays various roles in immunomodulation, inflammation, regulation of cell proliferation and differentiation, haematopoiesis, embryonic development, regeneration and wound healing. Moreover, as a neurotransmitter,
Amr M Mahdy FRCA MD is a Consultant Anaesthetist at Aberdeen Royal Infirmary and an Honorary Senior Lecturer at the University of Aberdeen, UK. Conflict of interest: none declared. Nigel R Webster FRCP FRCS is a Professor of Anaesthesia and Intensive Care at the University of Aberdeen, UK. Conflict of interest: none declared.
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uptake into the circulation. However, the DAO pathway is not active in the central nervous system.
The histamine H3 receptor is found mainly in the central nervous system (basal ganglia, hippocampus and cortical areas), but can also be found in the peripheral nervous system, airways, the cardiovascular system, and the gastrointestinal tract. Acting through presynaptic H3 receptor, histamine regulates its own release as well as the release of other neurotransmitters such as noradrenaline, dopamine, serotonin, acetylcholine, and gammaamino-butyric acid. In the lower airways, H3 receptors are located on postganglionic cholinergic nerves and defend against excess bronchoconstriction and in the upper airways, histamine may play a role in nasal congestion through its activity at H3 receptors. The H4 receptor has been detected in bone marrow, peripheral blood, spleen, thymus, lung, gastrointestinal tract, liver, peripheral nerves, and central neurones. Nevertheless, cells that clearly express functional H4 receptors are mainly haematopoietic and include: mast cells, eosinophils, basophils, dendritic cells, and T cells. H4 receptor activation induces calcium mobilization in mast cells and mediates mast cells migration towards histamine. Moreover the receptor plays a significant role in regulating dendritic and T-cell function. In general terms, the four histamine receptors can be described as heptahelical G-protein coupled receptors. They transduce extracellular signals through various G proteins, which function as mediators between the cell surface receptors and the intracellular second messenger systems. Histamine receptors exist in an equilibrium between two conformational states (Figure 1), active (R*) or inactive (R).
Histamine receptors Histamine exerts its diverse biologic effects through four types of receptors; H1, H2, H3 and H4 receptors (Table 1). Additionally, low-affinity intracellular non-H1, -H2, -H3, or -H4 receptors, have been recently described in cell nuclei and microsomes, although biologic functions at these receptors is still somewhat unclear. The H1 receptor is widely distributed throughout the body, with well-documented expression in the CNS, smooth muscle, sensory nerves, heart, adrenal medulla, and immune, endothelial, and epithelial cells. The H1 receptor mediates most of the postsynaptic effects of histamine within the central nervous system. Moreover, through its activity at H1 receptors, histamine stimulates smooth muscle contraction in the respiratory and gastrointestinal tract, stimulates sensory nerves leading to pruritus and sneezing, and increase vascular permeability leading to oedema. Simultaneous activation of H1 and H2 receptor can also result in hypotension, tachycardia, flushing, and headache. The H2 receptor is also widely expressed and can be found in gastric mucosal cells, heart, CNS, immune cells, and smooth muscles of the airway, vasculature, and uterus. H2 receptor activation stimulates hydrochloric acid secretion from the acidsecreting parietal cells of the gastric mucosa, leads to smooth muscle relaxation in the vasculature and airways, increases cardiac rate and contractility, and mediates some of the immunomodulatory effects of histamine.
Histamine receptor subtypes along with their selective agonists, inverse agonists/antagonists, G-protein coupling and signal transduction Receptor subtype
H1
H2
H3
H4
G-protein coupling Signal transduction
Gq/11
Gs
Gi/o
Gi/o
Phospholipase C activation / [ IP3 and DAG / [ Intracellular Ca and protein kinase C activation C Phospholipase A2 activation / [ Arachidonic acid C NOS activation C Phospholipase D activation
Adenylate cyclase activation / [ cAMP / Protein kinase A activation
C
C
Selective agonists
Histaprodifen
Amthamine Dimaprit Impromidine
Antagonists/ inverse agonists (examples)
Chlorphenamine Promethazine Loratidine Fexofenidine
Cimetidine Ranitidine Famotidine Nizatidine
Adenylate cyclase inhibi- C Adenylate cyclase inhibition / tion / Y cAMP Y cAMP C MAPK pathway activation C MAPK pathway activation C Phospholipase A2 activation / [ Arachidonic acid C Inhibition of Na/H exchanger C Y Intracellular Ca Clobenopropit (partial Alpha-Methyl-histamine agonist) Imetit Imetit Immepip Immepip 4-Methylhistamine Thioperamide JNJ-7777120 Pitolisant (ABT-288) VUF-6002 MK-0249 JNJ-17216498 C
IP3, inositol triphosphate; DAG, diacylglycerol; NOS, nitric oxide synthase; cAMP, cyclic adenosine monophosphate; MAPK, mitogen-activated protein kinase.
Table 1
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The two-state model of histamine receptors a
R
R
R*
c Inverse agonist
R
Agonist
b
Resting state
R*
Agonist
d True antagonist
R*
R
R*
(a) In the resting state, a balance exists between the active receptors R* and the inactive receptors R; (b) Agonists bind to the active state shifting the equilibrium towards R*; (c) Inverse agonists bind to the inactive state shifting the equilibrium towards R; (d) True antagonists bind to both active and inactive receptors interfering with agonist binding but with no effect on R/R* equilibrium. Figure 1
Moreover, they all have constitutive activity, which is defined as the ability to trigger downstream events even in the absence of ligand binding (receptors changing from R to R* in the absence of a ligand). Based on this two-state model, ligands at the histamine receptors can be classified into agonists (bind to the active state and shift the equilibrium towards R*), true antagonists (bind to both active and inactive state interfering with agonist binding but with no effect on equilibrium or intrinsic receptor activity), and inverse agonists (bind to the inactive state shifting the equilibrium towards R, and reduce the intrinsic activity of the receptor in the absence of an agonist). Most currently known antihistamines have been reclassified as inverse agonists and the term histamine antagonists is only reserved for those compounds that function as true antagonists. In the following paragraphs the term antihistamines is used to describe drugs with inverse agonist or antagonist activity at a given histamine receptor.
As mentioned earlier, the vast majority of H1 antihistamines exert their antihistaminic action by acting as inverse agonists at the H1 receptors; binding to and stabilizing the inactive state of the H1 receptor and reducing the intrinsic activity of the receptor even in the absence of an agonist. Based on their pharmacological structure, H1 antihistamines are traditionally classified into six groups: ethanolamines, ethylene diamines, alkylamines, piperazines, piperidines, and phenothiazines. This classification is, however, of limited clinical relevance, and currently H1 antihistamines are classified as ‘first generation’, also known as ‘sedating antihistamines’, and ‘second generation’, which are relatively non-sedating (Table 2). The terms ‘thirdgeneration’ and ‘new-generation’ antihistamines are sometimes used to describe some newly produced antihistamines that are selective isomers or active metabolites of older second-generation antihistamines. However, there is currently no consensus on such terminology, and for the purpose of this review these newer agents will still be considered as second-generation antihistamines. First-generation H1 antihistamines such as alimemazine, chlorphenamine, clemastine, cyproheptadine, hydroxyzine, and promethazine are non-selective in binding to the H1 receptor. Most of these drugs have weak antimuscarinic anticholinergic effects, some have alpha-adrenergic blocking effects (promethazine), and others can inhibit both histamine and 5hydroxytryptamine activity (cyproheptadine). Owing to their lipophilicity, relatively low molecular weight, and lack of recognition by the P-glycoprotein efflux pump, first-generation H1 antihistamines readily penetrate the non-fenestrated capillaries of the central nervous system (CNS; bloodebrain barrier)
H1 antihistamines In 1937, the first H1 antihistamine (thymo-ethyl-diethylamine) was synthesized. However, because of weak activity and high toxicity, this compound was not used in clinical practice. Clinically useful H1 antihistamines such as phenbenzamine, pyrilamine, and diphenhydramine were introduced in the 1940s. Currently, H1 antihistamines constitute the second most commonly used class of medications after antibiotics, with more than 40 varieties of H1 antihistamines used in clinical practice worldwide.
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Comparison between first- and second-generation H1 antihistamines
Receptor selectivity
Central H1 occupation Examples
Clinical uses
Side-effects
First generation
Second generation
Inverse agonists at H1 receptors Weak antimuscarinic a-Anti-adrenergic (promethazine) Anti-serotonergic (cyproheptadine) High occupancy Alimemazine Chlorphenamine Clemastine Cyproheptadine Hydroxyzine Promethazine Cyclizine Cinnarizine Allergic rhinitis Atopic dermatitis Acute and chronic urticaria Insect bites and stings Anaphylaxis (intravenous chlorphenamine) URT infection (no evidence) Insomnia Sedative premedication (promethazine) Vertigo and motion sickness (cinnarizine) Treatment/prevention of PONV (cyclizine) CNS depression (somnolence, impaired cognitive and psychomotor performance); other CNS effects (seizures, dyskinesia, dystonia, hallucinations) Anticholinergic effects (dry mouth, blurred vision, urine retention) Drugs of abuse Drugs of suicide and infants’ homicide Weight gain (cyproheptadine)
Highly selective for H1 receptors
0e30% occupancy Acrivastine Bilastine Cetirizine Levocetirizine (isomer of cetirizine) Loratadine Desloratadine (metabolite of loratadine) Mizolastine Fexofenadine (metabolite of terfenadine) Allergic rhinitis Atopic dermatitis Acute and chronic urticaria Insect bites and stings Seasonal asthma with allergic rhinitis URT infection (no evidence)
Minimal or no CNS depression Minimal or no anticholinergic effects Polymorphic ventricular tachycardias with torsade de pointes and ventricular fibrillation (astemizole and terfenadine; both not in clinical use)
CNS, central nervous system; URT, upper respiratory tract; PONV, postoperative nausea and vomiting.
Table 2
and bind to central H1 receptors, interfering with the actions of histamine on these receptors. Second-generation H1 antihistamines such as cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine and mizolastine have significantly less affinity for muscarinic cholinergic, alpha-adrenergic and 5-hydroxytryptaminergic receptors and penetrate poorly into the CNS because of their low lipid solubility, relatively high molecular weight and affinity for the Pglycoprotein efflux pump. Their propensity to occupy central nervous system H1 receptors varies from none for fexofenadine to 30% for cetirizine. H1 antihistamines, both first and second generation, have well-documented anti-allergic and anti-inflammatory effects. They exert these effects through their inverse agonist activity at peripheral H1 receptors and through other non-receptormediated mechanisms (e.g. inhibition of mast cell and basophil histamine release and inhibition of inflammatory cell activation). They are currently well established as first- or second-line treatments for a variety of allergic disorders.
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All H1 antihistamines are of potential value in the management of seasonal (intermittent) and perennial (persistent) allergic rhinitis in which they relieve nasal and conjunctival itching, sneezing and rhinorrhoea and improve the quality of life. They are also useful in the treatment of acute and chronic urticaria as they provide symptomatic relief of itching and reduce the number, size and duration of individual hives. However, the evidence for using first-generation drugs in the treatment of these disorders remains surprisingly small by current standards and most available evidence is derived from large randomized, controlled trials using second-generation drugs. Moreover, first-generation H1 antihistamines have an unsatisfactory benefit-to-risk ratio owing to their sedating effects, and although generally less expensive than second-generation drugs, when costs attributed to their adverse effects are considered, the difference may be less than expected. Second-generation H1 antihistamines should, therefore, be the preferred choice in the treatment of these disorders because of their lack of sedative, cognitive and psychomotor performanceimpairing and antimuscarinic anticholinergic adverse effects.
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H1 antihistamines are also used in the management of atopic dermatitis both for relief of itching and for their glucocorticoidsparing effects; however, the evidence in support of their efficacy is considerably weaker than it is in allergic rhinitis and urticaria. They are also administered to treat local allergic reactions to insect bites and stings. H1 antihistamines, usually in combination with a decongestant, are widely used to relieve symptoms in upper respiratory tract infections, otitis media and sinusitis. However, the published evidence does not support this practice and it is currently thought that the beneficial effects sometimes reported with firstgeneration drugs are due at least in part to their sedating and antimuscarinic effects. Similarly, current evidence does not support the use of H1 antihistamines in persistent asthma. However, in patients with allergic rhinitis and asthma, the use of second-generation H1 antihistamines has been shown to relieve co-existing mild seasonal asthma symptoms, reduce beta-2 adrenergic agonist requirements and improve pulmonary function. First-generation H1 antihistamines such as chlorphenamine and promethazine are used intravenously for the management of anaphylaxis when hypotension is unresponsive to epinephrine. Since most second-generation H1 antihistamines have low aqueous solubility, they are not available in formulations for injection and hence cannot be used in such circumstances. Owing to their ability to cross the bloodebrain barrier, firstgeneration H1 antihistamines such as promethazine are used as non-prescription sleeping aids; promethazine is commonly used as a sedative premedication in children; and cinnarizine, promethazine and cyclizine, are used for the prevention and treatment of symptoms of vertigo and motion sickness. Moreover, cyclizine has a well-established role in the prevention and management of postoperative nausea and vomiting. The anti-emetic effect of these drugs stems from their antimuscarinic properties and from their ability to block the histaminergic signal from the vestibular nucleus to the vomiting centre in the medulla. A wide variety of adverse effects has been attributed to firstgeneration H1 antihistamines. They readily penetrate the blood ebrain barrier and hence have the potential to cause CNS depression, which usually manifests as somnolence and impaired cognitive and psychomotor performance. Their use can also lead to a variety of other adverse CNS effects, including seizures, dyskinesia, dystonia and hallucinations. Firstgeneration H1 antihistamines have also been associated with fatalities in accidental or intentional overdose, and are potential agents of suicide and of infants’ homicide. Moreover, some firstgeneration H1 antihistamines are drugs of abuse leading to euphoria and hallucinations. First-generation H1 antihistamines commonly cause antimuscarinic anticholinergic effects such as dry mouth, blurred vision and dysfunctional urine voiding. Gastrointestinal upset, jaundice and pancytopenias have also been reported. Cyproheptadine causes appetite stimulation and inappropriate weight gain secondary to anti-serotonin effects. Second-generation H1 antihistamines are considerably less likely than first-generation drugs to cause adverse effects. In manufacturers’ recommended doses, the second-generation H1 antihistamines impair CNS function significantly less than the first-generation H1 antihistamines. Moreover, they lack any anticholinergic antimuscarinic effects. There are occasional
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reports of fixed-drug eruptions, exacerbations of existing urticaria and hepatitis after cetirizine or loratadine ingestion. Two early second-generation H1 antihistamines, astemizole and terfenadine, which are no longer approved, block the rapid component of delayed rectifier potassium current (IKr). As a result, these two agents potentially prolong the QT interval and may lead to cardiac arrhythmias, including polymorphic ventricular tachycardias with torsade de pointes and ventricular fibrillation. New second-generation H1 antihistamines such as cetirizine, desloratadine, fexofenadine and loratadine have 1:1000 of the potency in blocking the IKr current and are free of potential cardiac toxicity in therapeutic and supra-therapeutic doses. The weight of evidence to date suggests that the potential of second-generation H1 antihistamines to cause ventricular arrhythmias is not a class effect.
H2 antihistamines In the 1960s, it became clear that ‘traditional antihistamines’ do not antagonize the stimulatory effect of histamine on gastric acid secretion, which lead to the assumption that histamine mediates its effect through two receptor subtypes designated H1 and H2 receptors. This hypothesis became generally accepted and the search for H2-specific antihistamines soon began. In 1969, burimamide, the first H2 antihistamine was discovered; however it was insufficiently potent for oral administration. Further modification of burimamide led to the development of metiamide, which was an effective agent; however, it was not suitable for clinical practice because of its bone marrow toxicity and nephrotoxicity. Further investigations into the activity and toxicity of similar compounds led to the discovery of cimetidine, which was the first clinically useful H2 antihistamine. This was followed by ranitidine, famotidine and nizatidine. Like H1 antihistamines, H2 antihistamines are inverse agonists and not true H2 antagonists, as was previously thought. They exert their antihistaminic effects by binding to, and stabilizing, the inactive state of the H2 receptor. Moreover, in the absence of histamine, these drugs can inhibit the constitutive activity of H2 receptors. H2 antihistamines inhibit the chronotropic, inotropic and delayed vasodilatory effects of histamine, and, of particular therapeutic importance, suppress basal and stimulated acid secretion by parietal cells. They accomplish the latter effect through their inverse agonist activity at the H2 receptors of the parietal cells, thus opposing the effects of histamine released by the enterochromaffin-like cells of the stomach. Moreover, these compounds attenuate the stimulatory effects of gastrin and acetylcholine on gastric acid production. The four H2 antihistamines are currently available over the counter in relatively low doses, and have become extremely popular in relieving the symptoms of gastro-oesophageal reflux disease (heart burn). As prescription medications, H2 antihistamines alone are not generally effective for more severe grades of gastrooesophageal reflux disease; however, they are still recommended and used widely for patients with mild or infrequent symptoms, and also, in combination with proton pump inhibitors for patients with persistent nocturnal symptoms. They are also used in the treatment of functional dyspepsia, but caution should be exerted as the regular use of these medications in uninvestigated dyspepsia can mask the symptoms of gastric malignancy in elderly patients.
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serotonin, norepinephrine and gamma-amino-butyric acid. These effects could be of potential benefit in the treatment of sleep disorders, attention-deficit hyperactivity disorder, dementias, schizophrenia, and Alzheimer’s disease. Moreover, the peripheral actions of H3 antihistamine might prove to be of value in relieving nasal congestion in patients with allergic rhinitis. One of the most advanced H3 antihistamines in clinical development is the nonimidazole-based inverse agonist pitolisant (formerly known as tripolisant; BF2.649). Pitolisant has been granted orphan drug status by the European Medicine agency for the treatment of excessive diurnal sleepiness in patients with narcolepsy, Parkinson’s disease, and obstructive sleep apnoea/ hypopnoea. Several H3 antihistamine compounds are still undergoing phase I and phase II clinical trials. Compounds with an agonist activity at the H3 receptor are also being developed. These compounds can increase histamine and dopamine release and might be useful in the management of insomnia, migraine and schizophrenia.
H2 antihistamines can also be used to promote healing of nonsteroidal anti-inflammatory drug-associated ulcers, and have been used in high doses in ZollingereEllison syndrome; however, proton pump inhibitors are currently the first option in treating such conditions. In Helicobacter pylori-induced ulcers, maintenance treatment with low-dose H2 antihistamines has largely been replaced by eradication regimens involving the use of proton pump inhibitors, clarithromycin and either amoxicillin or metronidazole. These eradication regimens are usually effective in healing ulcers caused by H. pylori and treatment is seldom required for more than 4 weeks. However, in high-risk patients (e.g. those with a history of complications, frequent recurrences, ulcers testing negative for H. pylori, refractory giant ulcers, or severely fibrosed ulcers), maintenance therapy with H2 blockers or proton pump inhibitors is still indicated. H2 antihistamines are also used prophylactically to reduce the incidence of stress-related gastrointestinal bleeding (stressinduced ulcers) in intensive care patients, to reduce the frequency of bleeding from gastroduodenal erosions in hepatic coma, and to reduce the risk of acid aspiration in obstetric patients. They are also sometimes administered as a premedication before elective surgery to reduce the risk of acid aspiration; however, there is currently no evidence to support the latter practice. H2 antihistamines can also be used, off label, in combination with an H1 antihistamine in patients with acute and chronic urticaria that is refractory to treatment with an H1 antihistamine alone. Moreover, they can also be administered concomitantly with an H1 antihistamine in patients with anaphylaxis whose hypotension is unresponsive to epinephrine. In the latter case, H1 antihistamine should be given first, as rapid intravenous administration of cimetidine or ranitidine alone may exacerbate the hypotension and induce cardiac dysrhythmias. H2 antihistamines have a good safety record and are generally well tolerated. Side-effects include diarrhoea and gastrointestinal disturbances, altered liver function tests, headache, dizziness, rash and tiredness. Rare side-effects include acute pancreatitis, bradycardia, AV block, confusion, depression and hallucinations, particularly in the elderly. Hypersensitivity reactions, including fever, arthralgia, myalgia and anaphylaxis, and blood disorders, including agranulocytosis, leucopenia, pancytopenia and thrombocytopenia, have also been reported. Additionally, gynaecomastia, loss of libido and impotence have been reported in patients receiving cimetidine. Cimetidine is also a well-known inhibitor of the cytochrome P450 enzymes and therefore has the capacity to reduce the metabolism of drugs that are metabolized by these enzymes if given concomitantly. This is particularly relevant in patients receiving warfarin, phenytoin and theophylline, and hence cimetidine should be avoided in this group of patients.
H4 antihistamines The H4 receptor is the newest member of the histamine receptor family and, in contrast to other histamine receptors, it has a distinct expression profile on mast cells, eosinophils, dendritic cells and T lymphocytes. The H4 receptor plays a significant role in modulating a range of physiological functions of immune cells, including chemotaxis, cytokine release and adhesion molecule expression. Moreover, the use of H4 antihistamines in animal models of colitis, asthma and pruritus has already produced some promising results. It is therefore hoped that H4 antihistamines will be of therapeutic benefit in the management of various immune and inflammatory disorders in the future. Moreover, some recent evidence supports a novel role of the histamine H4 receptor in cancer progression representing a promising molecular target and avenue for cancer drug development. Alcaftadine is a new antihistamine with combined antagonist activity at histamine H1, H2, and H4 receptors. It significantly reduces itching, eosinophil recruitment and redness after exposure to an allergen. Alcaftadine was recently approved by the FDA for the prevention of itching associated with allergic conjunctivitis. A FURTHER READING Bernstein JA. Antihistamines. In: Grammer Leslie C, Greenberger Paul A, eds. Patterson’s allergic diseases. 7th edn. Lippincott Williams and Wilkins, 2009; 561e73. British Medical Association and the Royal Pharmaceutical Society of Great Britain. British national formulary. London: BMJ Publishing Group & RPS Publishing, 2014. Golightly LK, Greos LS. Second-generation antihistamines: actions and efficacy in the management of allergic disorders. Drugs 2005; 65: 341e84. Schwartz JC. The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol 2011; 163: 713e21. Simons FER. Advances in H1-antihistamines. N Engl J Med 2004; 351: 2203e18. Zampeli E, Tiligada E. The role of histamine H4 receptor in immune and inflammatory disorders. Br J Pharmacol 2009; 157: 24e33.
H3 antihistamines The successful cloning and functional expression of the histamine H3 receptor in the late 1990s facilitated the efforts of several pharmaceutical companies in developing a host of potential drugs that can therapeutically modulate the function of this receptor. In animal models, H3 antihistamines counteract the effects of histamine on presynaptic H3 receptors, and enhance the release of several neurotransmitters including histamine, dopamine,
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