Antihistamine Drugs
Yesim Yilmaz-Demirdag
Sanaa A. Mahmoud
Sami L. Bahna
Antihistamines are among the most frequently used medications worldwide. As a body chemical, histamine has a role in health as well as in a variety of diseases. This chapter describes the physiologic role and the pathologic consequences of histamine release. The histamine receptors and their various functions are reviewed, and the clinical pharmacology and therapeutic uses of H1 antihistamines are summarized. Antagonists to H2 and H3 receptors as well as the H4 receptors are briefly discussed.
Historical Background
Histamine, initially called β-aminoethylimidazole, was first discovered as a constituent of ergot and then was chemically synthesized in 1907 (1). Soon after, Dale and Laidlaw (2,3) discovered that histamine stimulated a host of smooth muscle cells and had an intense vasodilator action. In their experiments, they found that histamine induced shock-like syndrome in frogs and mammals. Histamine caused bronchospasm, myocardial contraction, and cardiac and pulmonary vasoconstriction. It also caused a fall in the systemic blood pressure due to capillary dilation resulting in pooling of blood in the capillary bed and a substantial extravascular loss of plasma.
In 1927, Best and coworkers (4) isolated histamine from fresh samples of liver and lung establishing that this amine is a natural constituent of the body. Demonstration of its presence in a variety of other tissues soon followed, hence its name after the Greek word “histos” for tissues. In the same year, Lewis (5) further expanded on the vascular effects of histamine, which suggested that this mediator could be released from cells in the skin on stimulation with appropriate trauma causing the “wheal-and-flare response,” which is also known as “the triple wheal-and-flare response.” This reaction includes an immediate local reddening due to vasodilatation, a wheal due to increased vascular permeability and a flare response due to indirect vasodilatation secondary to axonal reflex. In 1952, Riley and West (6) discovered that the mast cell is the major source for histamine. Later they showed a correlation between the number of mast cells and the histamine content in a variety of animal tissues as well as in urticaria pigmentosa lesions in humans (7). They also found histamine in the circulating basophils. In 1953, Mongar and Schild (8) published the first series of studies concerning the mechanism of histamine release from mast cells. Subsequent studies focused on the role of calcium in histamine release by antigens and other ligands (9).
Histamine
Synthesis, Storage, and Metabolism of Histamine
Histamine is a hydrophilic molecule comprising an imidazole ring and an amino group connected by two methylene groups (10). Histamine occurs in plants as well as in animal tissues and is a component of some venoms and a variety of insect secretions. It is synthesized in the Golgi apparatus of mast cells and basophils by decarboxylation of a semi-essential amino acid L-histidine, a reaction catalyzed by the enzyme histamine decarboxylase. Once formed, histamine is either stored in the cytoplasmic granules of mast cells (and basophils) or rapidly inactivated. Histamine is mostly (70%) metabolized through methylation by N-methyltransferase to N-methyl histamine and partly (30%) through oxidation by diamine oxidase to imidazole acetic acid (11). A very small amount of released histamine (2% to 3%) is excreted in the urine unchanged. The turnover of histamine in the mast cell secretory granules is slow. When histamine is depleted from its stores, it may take weeks before its concentration returns to normal levels. Histamine metabolites have little or no activity and are excreted in the urine.
The main site of histamine storage in most tissues is the mast cell. The latter is found in the loose connective tissue of all organs, especially around blood vessels, nerves, and lymphatics. It is most abundant in the shock organs of allergic diseases, namely the skin and the mucosa of the respiratory and the gastrointestinal tracts (12). The human heart contains large numbers of mast cells, localized primarily in the wall of the right atrium (13). In addition to mast cells and basophils, histamine is present in the epidermis, enterochromaffin cells of the fundus of the stomach, and neurons within the central nervous system (CNS) (10,14).
Histamine Receptors
To date, four distinct types of receptors have been demonstrated. The existence of more than one type of histamine receptor was suggested in 1966 by Ash and Schild (15) who noted that the classic antihistamine mepyramine could block histamine-induced contractions of guinea pig ileum but not histamine-induced gastric acid secretion. The effects of histamine on H1, H2, H3, and H4 receptors and their distributions in humans are presented in Table 39.1. Human H1 receptors have approximately 45% homology with muscarinic receptors (16).
The H3 receptor was identified in 1983 (17) and its gene was cloned in 1999 (18). It acts as a presynaptic autoreceptor and is expressed in the central and peripheral nervous systems where it modulates neurotransmission. It has been recently shown that H3 receptors are involved in the blood–brain barrier function and may play a favorable role in neuroinflammation (19). H3 agonists (e.g., imetit and immepip) decrease histamine release and thus might be useful in the treatment of a variety of gastrointestinal, cardiac, and neurologic disorders (e.g., migraine and schizophrenia) (20).
Effects of Histamine
Cardiovascular
Injection of histamine in human causes a decrease in blood pressure and an increase in the heart rate. The blood pressure drops because of the direct vasodilator action on the arterioles and precapillary sphincters. The increase in heart rate results from a direct stimulatory action on the myocardium, mainly through the H2 receptors, as well as through a reflex-compensatory tachycardia secondary to hypotension (14). Both H1 and H2 receptors seem to be involved in these responses; hence, a combination of H1 and H2 antihistamines is often more effective in preventing the cardiovascular effects of histamine than either alone.
Table 39.1 Histamine Receptor Types | ||||||||||||||||||||||||||||||||||||||||
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Stimulation of H1 receptors in the atrioventricular node slows down the heart rate by decreasing atrioventricular nodal conduction (24). Cardiac H1 receptors are also found in epicardial coronary vessels where they mediate vasoconstriction (25). H2 receptors are found in the coronary
vasculature, where their vasodilator action opposes that of H1 receptors (25). H2 receptors are also widely distributed throughout the myocardium and nodal tissue where they exert positive inotropic and chronotropic effects, respectively (24,25). H3 receptors in the heart are present in the presynaptic postganglionic sympathetic fibers and are autoinhibitory to presynaptic norepinephrine release (26,27). The widespread distribution of histamine receptors throughout the myocardium, nodal tissue, and coronary vasculature suggests a significant role in the physiologic regulation of the normal healthy heart. Nault and coworkers (28) reported that H1 antihistamines (loratadine) in young healthy subjects did not alter the autonomic cardiovascular control. However, an H2 antihistamine (ranitidine) altered cardiac sympathovagal balance when administered alone. Such a finding indicates a shift toward sympathetic predominance in heart rate regulation, with a potential of inducing arrhythmias.
vasculature, where their vasodilator action opposes that of H1 receptors (25). H2 receptors are also widely distributed throughout the myocardium and nodal tissue where they exert positive inotropic and chronotropic effects, respectively (24,25). H3 receptors in the heart are present in the presynaptic postganglionic sympathetic fibers and are autoinhibitory to presynaptic norepinephrine release (26,27). The widespread distribution of histamine receptors throughout the myocardium, nodal tissue, and coronary vasculature suggests a significant role in the physiologic regulation of the normal healthy heart. Nault and coworkers (28) reported that H1 antihistamines (loratadine) in young healthy subjects did not alter the autonomic cardiovascular control. However, an H2 antihistamine (ranitidine) altered cardiac sympathovagal balance when administered alone. Such a finding indicates a shift toward sympathetic predominance in heart rate regulation, with a potential of inducing arrhythmias.
Histamine-induced vasodilation causes transudation of fluid and even large molecules such as proteins into the perivascular tissue resulting in skin hives or mucosal edema associated with allergic reactions. The vasodilator effect of histamine is mediated by both H1 and H2 receptors located on different cell types in the vascular bed: H1 receptors on the vascular endothelium and both H1 and H2 receptors on the smooth muscle cells (10).
Activation of H1 receptors leads to increased intracellular Ca2+, activation of phospholipase A2, and the local production of nitric oxide, an endothelium-derived relaxing factor (29). Nitric oxide diffuses to the smooth muscle cell, where it activates a soluble guanylyl cyclase and causes accumulation of cyclic guanosine monophosphate (cGMP). The cGMP-dependent protein kinase release and a decrease in intracellular Ca2+ seem to be involved in the smooth muscle relaxation caused by this cyclic nucleotide.
Nonvascular Smooth Muscle
Histamine-induced bronchospasm has been demonstrated in both humans and guinea pigs. Although some H2 receptors are present in human bronchial smooth muscle, their dilator effect is much dominated by the spasmogenic influence of H1 receptors. In asthma, histamine-induced bronchospasm may involve an additional reflex component that arises from irritation of afferent vagal nerve endings (10).
Histamine has lesser effects on nonbronchial smooth muscle. It causes various degrees of uterine muscle contraction, but such an effect is negligible on the human uterus, gravid or not. The response of the intestinal muscle varies according to the species and region but is primarily contraction. The effect on other smooth muscles (e.g., urinary bladder, ureter, gall bladder, and iris) is minimal or inconsistent.
Gastric Acid Secretion
Histamine stimulates gastric acid secretion by the parietal cells through H2 receptors as well as stimulation of vagal reflex and gastrin release (30). It also increases the output of pepsin and the intrinsic factor. The activation of H2 receptors on the parietal cells leads to increase in adenyl cyclase activity, cyclic adenosine monophosphate (cAMP) concentration, and intracellular Ca2+.
Central Nervous System
Histaminergic neurons have been identified in some areas of the brain. H1 receptors are found throughout the CNS and are densely concentrated in the hypothalamus. Histamine acts as a neurotransmitter along with the other biogenic amines, serotonin, dopamine, norepinephrine, and acetylcholine (31). Histamine increases wakefulness and inhibits appetite through H1 receptors. Neuronal histamine is involved in arousal, learning, memory, locomotor activity, food intake, and other physiologic processes.
Presynaptic H3 receptors play important role in inhibiting the synthesis and release of histamine in the histaminergic neurones in the CNS. H3-receptor agonists (e.g., (R)-α-methylhistamine, imetit, and immepip) reduce the release of several amines in various areas of the brain, including histamine, norepinephrine, dopamine, 5-hydroxytryptamine, and possibly acetylcholine (14).
Immune System and Inflammatory Response
A recent review on the role of histamine in immunologic and allergic inflammation has been published (32). Many inflammatory cells express H1, H2, and H4 receptors. The H4 receptor is found more on the dendritic cells, mast cells, eosinophils, monocytes, basophils, and T cells. In general, H1 receptors stimulate proinflammatory activity through increased cell migration to areas of inflammation, whereas H2 receptors act as a potent suppressor of inflammatory and effector functions. Histamine also facilitates several proinflammatory activities through H4 receptors. Most ligands that target H1 and H2 receptors have little affinity for H4 receptors. The H4 receptor may play a role in chemotaxis of mast cells, eosinophils, and dendritic cells. The role of the H4 receptor in inflammatory and pruritic response has been verified in vivo (33,34,35).
Allergy Response
Histamine release occurs when allergen binds to the specific immunoglobulin E (IgE) molecule on the mast cells and basophils in previously sensitized individuals. Histamine release from these cells depends on the rise in intracellular Ca2+ (10). Although histamine was the first identified mediator of allergic inflammation, numerous other mediators exist. They are either preformed in the granules (e.g., serotonin, tryptase, chymases, carboxypeptidases, acid hydrolases, oxidative enzymes, chemotactic factors, and proteoglycans such as heparin and chondroitin sulfate) or newly formed from the mast cell membrane (e.g., prostaglandin D2 and leukotrienes).
Elevated plasma histamine levels are present in conditions associated with increased mast cell number (e.g., mastocytosis) or activation (e.g., anaphylaxis or other allergic diseases) (36). Increased histamine levels have also been noted in the skin and plasma of patients with atopic dermatitis and in chronic urticaria (37,38,39). Recently, it was demonstrated that a special type of dendritic cells (the inflammatory dendritic epidermal cells), express H4 receptors in
skin lesions of atopic dermatitis (23). Increased levels of histamine have been found in bronchoalveolar lavage fluid in patients with asthma (40). However, H1 and H2 blockers have minimal therapeutic effect in asthma, suggesting a possible role of H4 receptors.
skin lesions of atopic dermatitis (23). Increased levels of histamine have been found in bronchoalveolar lavage fluid in patients with asthma (40). However, H1 and H2 blockers have minimal therapeutic effect in asthma, suggesting a possible role of H4 receptors.
Extrinsic Factors Causing Direct Histamine Release
A large number of agents cause direct histamine release from mast cells without prior sensitization or involvement of specific antibodies. These include peptides that contain basic amino acids (arginine and/or lysine), complement derivatives (C3a, C4a, and C5a), substance P, hymenoptera venom constituents such as melittin, and chemicals and therapeutic agents such as morphine, codeine, dextrans, blood substitutes, polymyxin B, radiocontrast media, quaternary ammonium compounds, pyridinium compounds, piperidines, alkaloids, and plasma expanders. Basically, pathways that result in a decrease in cAMP or pathways that result in an increase in cGMP will cause histamine release. The flushing and hypotension (the red-man syndrome) that often occurs during vancomycin infusion is probably due to direct histamine release (41). Various degrees of direct histamine release may also occur in certain individuals in response to particular foods (e.g., tomatoes, strawberries) or physical agents (e.g., dermographism) (42).
Antihistamine Preparations
Development of antihistamines for allergy, gastric ulcers, motion sickness, and insomnia has utilized the diverse actions of histamine. These drugs have been so successful and widely used that the term “antihistamine” has become commonplace and mostly refer to H1 antihistamines. In general, an antihistamine to a particular type of histamine receptor is not effective against the others. Since allergic reactions are primarily mediated through the activation of H1 receptors, emphasis in this chapter will be given to H1 antihistamines more than to the other types of antihistamines.
For years it was believed that H1 antihistamines acted through competition with histamine for the receptors. Recent research showed that H1 receptors exist in both active and inactive isoforms that are in equilibrium on the cellular surface and respond to the agonist (histamine) and inverse agonists (antihistamines), respectively (43). In other words, antihistamines act as inverse agonists that bind and stabilize the inactive form of the receptor shifting the equilibrium to the inactive state. This new understanding is rather important.
H1 Antihistamines
The first H1 antihistamine, compound F929, was discovered in 1937 by Staub and Bovet (44). Shortly afterwards, Halpern in 1942 developed the first antihistamine for human use, phenbenzamine (Antergan) (45). Later diphenhydramine and numerous other preparations became available. Most H1 antihistamines are stable, water-soluble salts and have similar pharmacologic actions and therapeutic applications. In general, the molecular structure of H1 antihistamines comprises a double-aromatic unit linked by a two- or three-atom chain attached to a tertiary amino basic group. The histamine molecule has similar structure but differs from antihistamines (i.e., inverse agonists) in possessing only one aromatic (imidazole) unit and in being levorotatory, whereas antihistamines are dextrorotatory.
H1 antihistamines have been traditionally classified into six groups: the ethanolamines, ethylenediamines, alkylamines, piperazines, piperidines, and phenothiazines. With the development of newer “nonsedating” preparations, they are generally classified as first- and second-generation antihistamines (Table 39.2). Some of the second-generation preparations are active metabolites of first-generation compounds; for example, fexofenadine, levocetirizine, and desloratadine are active metabolites of terfenadine, cetirizine, and loratadine, respectively.
Table 39.2 Chemical and Functional Classifications of H1 Antihistamines | |||||||||||||||||||||||||||||||||||||||
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Pharmacologic Properties of H1 Antihistamines
In general, first-generation H1 antihistamines are rapidly absorbed and metabolized. Their binding to the receptors is readily reversible by spontaneous dissociation or by high levels of histamine. Most first-generation antihistamines have a short duration of action and optimally may need to be administered every 4 to 6 hours. Because of their lipophilicity and low molecular weight, they easily cross the blood–brain barrier, bind to the H1 receptors, and create their CNS side effects (Table 39.3), primarily sedation, but in certain subjects CNS stimulation may occur.
The second-generation H1 antihistamines are lipophobic and have high molecular weights and thus do not easily cross the blood–brain barrier, with minimal CNS adverse effects (16,46). They have longer duration of action (12 to 24 hours) because they strongly bind to the receptors and dissociate slowly (47). To date, at least 11 second-generation anti-H1 preparations were studied in double-blind, placebo-controlled studies in children.
Almost all first-generation H1 preparations have some antimuscarinic effect. Even at usual doses, they often cause dryness of the mucous membranes and sometimes urinary retention or blurred vision. Certain first-generation H1 antihistamines, particularly promethazine, have α-adrenergic blocking ability (14). Others may exhibit antiserotonin activity (e.g., cyproheptadine) (14) or antidopamine effect (e.g., phenothiazines) (48). In high concentrations, some H1 antihistamines, particularly promethazine, have a local anesthetic effect that can be more potent than procaine (10). Some CNS effects can be of therapeutic value, for example, dimenhydrinate and diphenhydramine for motion sickness and diphenhydramine in decreasing drug-induced extrapyramidal symptoms. Over the last two decades, some H1-antihistamines have been found to have antiallergic, anti-inflammatory properties apart from their action on H1 receptors (49,50). They downregulate allergic inflammation either by direct activation of H1 receptors or indirectly through nuclear factor κB by suppressing antigen presentation, expression of proinflammatory cytokines and cell adhesion molecules, and chemotaxis. These antiallergic properties are believed to be due to their suppression of mast cell and basophil activity (51,52).
Table 39.3 Mechanism of Common Side Effects of H1 Antihistamines | |||||||||||||||||
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In addition to variation in their H1-blocking activity and anti-inflammatory properties, the effect of H1 antihistamines on various target organs varies widely, probably due to differences in their tissue deposition capacity. Moreover, it seems that the response, in terms of clinical efficacy and side effects, to any particular anti-H1 medication varies from one patient to another (53). Such heterogeneity in response can be due to gene abnormalities in the synthetic and/or metabolic pathways or in the receptors (54,55). Polymorphisms of the enzymes in the metabolic pathway could enhance or delay their degradation. For example, one single nucleotide polymorphism for histamine N-methyltransferase, C314 T, results in decrease in enzyme activity and is found in 5% to 10% of the general population (56).
Desloratadine has better pharmacokinetics and lesser drug–drug interactions than its parent drug loratadine. Also, levocetirizine has better receptor affinity and selectivity than cetirizine.
Pharmacokinetics of H1 Antihistamines
Comparative pharmacology of H1 antihistamines has been reviewed recently (57). For most first-generation H1 antihistamines, the pharmacokinetics (absorption, distribution, metabolism, and eliminations) has not been optimally investigated. Pharmacodynamic studies (correlations between drug concentrations and activity) were carried out for only a few preparations. Furthermore, first-generation H1 antihistamines have not been investigated in young children or in patients with renal or hepatic insufficiency. Also, there are only a few studies regarding drug–drug and drug–food interactions (Table 39.4).
Most antihistamines are well absorbed from the gastrointestinal tract, achieving peak plasma concentration generally in 1 to 3 hours, with a therapeutic effect usually for 4 to 6 hours, and may last up to 24 hours for the newer preparations (10). The clinical effect persists even though the serum concentration of the parent compound has declined to the lowest limit of analytical detection, which suggests a continued action by active metabolites in the tissues. For some antihistamines, such as fexofenadine, bioavailability can be affected by the coadministration of foods such as grapefruit or bitter orange juice (58) or of other drugs such as verapamil, probenecid, and cimetidine (59).
Drug clearance is a measure of elimination. It is the volume of plasma that is completely cleared of the drug within a given period of time and is expressed as volume/time. The total body clearance of H1 antihistamines is the sum of clearance from all organs and includes both hepatic and renal clearances. The clearance rate and plasma half-life vary widely from one preparation to another. The half-life is a measure of the time during which the drug plasma concentration decreases by 50%. H1 antihistamines have half-life ranging from less than 24 hours up
to a few days in children (60,61) and up to several days in adults (62,63) (Table 39.4).
to a few days in children (60,61) and up to several days in adults (62,63) (Table 39.4).
Table 39.4 Pharmacokinetics, Formulations, and Pediatric Doses of H1 Antihistamines | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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