Goodman and Gilman Manual of Pharmacology and Therapeutics

Section IV
Inflammation, Immunomodulation, and Hematopoiesis

chapter 32
Histamine, Bradykinin, and Their Antagonists

Histamine is a major mediator of inflammation, anaphylaxis, and gastric acid secretion; in addition, histamine plays a role in neurotransmission. Our understanding of the physiological and pathophysiological roles of histamine has been enhanced by the development of subtype-specific receptor antagonists and by the cloning of 4 receptors for histamine. Competitive antagonists of H1receptors are used therapeutically in treating allergies, urticaria, anaphylactic reactions, nausea, motion sickness, insomnia, and some symptoms of asthma. Antagonists of the H2 receptor are effective in reducing gastric acid secretion. The peptide, bradykinin, has cardiovascular effects similar to those of histamine and plays prominent roles in inflammation and nociception.

HISTAMINE

Histamine is a hydrophilic molecule consisting of an imidazole ring and an amino group connected by an ethylene group, biosynthesized from histidine by decarboxylation (Figure 32–1). The 4 histamine receptors, all GPCRs, can be differentially activated by analogs of histamine and inhibited by specific antagonists (Table 32–1).

Table 32–1

Characteristics of Histamine Receptors

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Figure 32–1 Histamine synthesis and metabolism in humans. Histamine is synthesized from histidine by decarboxylation. Histamine is metabolized via 2 pathways, predominantly by methylation of the ring followed by oxidative deamination (left side of figure), and secondarily by oxidative deamination and then conjugation with ribose. These metabolites have little or no activity and are excreted in the urine. Measurement of urinary N-methylhistamine affords a reliable index of histamine production. Artifactually elevated levels of histamine in urine arise from genitourinary tract bacteria that can decarboxylate histidine. MAO, monoamine oxidase.

DISTRIBUTION AND BIOSYNTHESIS

DISTRIBUTION. Almost all mammalian tissues contain histamine in amounts ranging from <1 to >100 μg/g. Concentrations in plasma and other body fluids generally are very low, but human cerebrospinal fluid (CSF) contains significant amounts. The concentration of histamine is particularly high in tissues that contain large numbers of mast cells, such as skin, bronchial mucosa, and intestinal mucosa.

SYNTHESIS, STORAGE, AND METABOLISM. Histamine is formed by the decarboxylation of the amino acid histidine by the enzyme L-histidine decarboxylase (see Figure 32–1). Mast cells and basophils synthesize histamine and store it in secretory granules. At the secretory granule pH of ~5.5, histamine is positively charged and ionically complexed with negatively charged acidic groups on other granule constituents, primarily proteases and heparin or chondroitin sulfate proteoglycans. The turnover rate of histamine in secretory granules is slow. Non–mast cell sites of histamine formation include the epidermis, the gastric mucosa, neurons within the CNS, and cells in regenerating or rapidly growing tissues. Turnover is rapid at these non–mast cell sites because the histamine is released continuously rather than stored. Non–mast cell sites of histamine production contribute significantly to the daily excretion of histamine metabolites in the urine. Because L-histidine decarboxylase is an inducible enzyme, the histamine-forming capacity at such sites is subject to regulation. Histamine that is ingested is rapidly metabolized, and the metabolites are eliminated in the urine.

RELEASE AND FUNCTIONS OF ENDOGENOUS HISTAMINE

Histamine is released from storage granules as a result of the interaction of antigen with immunoglobulin E (IgE) antibodies on the mast cell surface. Histamine plays a central role in immediate hypersensitivity and allergic responses. The actions of histamine on bronchial smooth muscle and blood vessels account for many of the symptoms of the allergic response. In addition, some drugs act directly on mast cells to release histamine, causing untoward effects. Histamine has a major role in regulating gastric acid secretion and also modulates neurotransmitter release.

ROLE IN ALLERGIC RESPONSES. The principal target cells of immediate hypersensitivity reactions are mast cells and basophils. As part of the allergic response to an antigen, IgE antibodies are generated and bind to the surfaces of mast cells and basophils via specific high-affinity Fc receptors. This receptor, FcεRI, consists of α, β, and 2 γ chains (see Chapter 35). Antigen bridges the IgE molecules and via FcεRI activates signaling pathways in mast cells or basophils involving tyrosine kinases and subsequent phosphorylation of multiple protein substrates within 5-15 sec of contact with antigen. These events trigger the exocytosis of the contents of secretory granules.

RELEASE OF OTHER AUTACOIDS. Stimulation of IgE receptors also activates phospholipase A2 (PLA2), leading to the production of a host of mediators, including platelet-activating factor (PAF) and metabolites of arachidonic acid such as leukotrienes C4 and D4, which contract the smooth muscles of the bronchial tree.

HISTAMINE RELEASE BY DRUGS, PEPTIDES, VENOMS, AND OTHER AGENTS. Many compounds, including a large number of therapeutic agents, stimulate the release of histamine from mast cells directly and without prior sensitization. Responses of this sort are most likely to occur following intravenous injections of certain categories of substances. Tubocurarine, succinylcholine, morphine, some antibiotics, radiocontrast media, and certain carbohydrate plasma expanders also may elicit the response. The phenomenon is one of clinical concern, and may account for unexpected anaphylactoid reactions. Basic polypeptides often are effective histamine releasers, and over a limited range, their potency generally increases with the number of basic groups. For example, bradykinin is a poor histamine releaser, whereas kallidin (Lys-bradykinin) and substance P, with more positively charged amino acids, are more active. Some venoms, such as that of the wasp, contain potent histamine-releasing peptides. Basic polypeptides released upon tissue injury constitute pathophysiological stimuli to secretion for mast cells and basophils.

Within seconds of the intravenous injection of a histamine liberator, human subjects experience a burning, itching sensation. This effect, most marked in the palms of the hand and in the face, scalp, and ears, is soon followed by a feeling of intense warmth. The skin reddens, and the color rapidly spreads over the trunk. Blood pressure falls, the heart rate accelerates, and the subject usually complains of headache. After a few minutes, blood pressure recovers, and crops of hives usually appear on the skin. Colic, nausea, hypersecretion of acid, and moderate bronchospasm also frequently occur. Histamine liberators do not deplete tissues of non–mast cell histamine.

INCREASED PROLIFERATION OF MAST CELLS AND BASOPHILS AND GASTRIC CARCINOID TUMORS. In urticaria pigmentosa (cutaneous mastocytosis), mast cells aggregate in the upper corium and give rise to pigmented cutaneous lesions that sting when stroked. In systemic mastocytosis, overproliferation of mast cells also is found in other organs. Patients with these syndromes suffer a constellation of signs and symptoms attributable to excessive histamine release, including urticaria, dermographism, pruritus, headache, weakness, hypotension, flushing of the face, and a variety of GI effects, such as diarrhea or peptic ulceration. Gastric carcinoid tumors secrete histamine, which is responsible for episodes of vasodilation as part of the patchy “geographical” flush.

GASTRIC ACID SECRETION. Histamine acting at H2 receptors is a powerful gastric secretagogue, evoking a copious secretion of acid from parietal cells (see Figure 45–1); it also increases the output of pepsin and intrinsic factor. The secretion of gastric acid from parietal cells also is caused by stimulation of the vagus nerve and by the enteric hormone gastrin. However, histamine undoubtedly is the dominant physiological mediator of acid secretion; blockade of H2 receptors not only antagonizes acid secretion in response to histamine but also inhibits responses to gastrin and vagal stimulation (see Chapter 45).

CNS. Histamine-containing neurons control both homeostatic and higher brain functions, including regulation of the sleep-wake cycle, circadian and feeding rhythms, immunity, learning, memory, drinking, and body temperature. However, no human disease has yet been directly linked to dysfunction of the brain histamine system. Histamine, histidine decarboxylase, enzymes that metabolize histamine, and H1, H2, and H3 receptors are distributed widely but non-uniformly in the CNS. H1 receptors are associated with both neuronal and non-neuronal cells and are concentrated in regions that control neuroendocrine function, behavior, and nutritional state. Distribution of H2 receptors is more consistent with histaminergic projections than H1 receptors, suggesting that they mediate many of the postsynaptic actions of histamine. H3 receptors also are concentrated in areas known to receive histaminergic projections, consistent with their function as presynaptic autoreceptors. Histamine inhibits appetite and increases wakefulness via H1 receptors.

PHARMACOLOGICAL EFFECTS

RECEPTOR–EFFECTOR COUPLING AND MECHANISMS OF ACTION. Histamine receptors are GPCRs, coupling to second messenger systems and producing effects as noted in Table 32–1.

H3 and H4 receptors have a much higher affinity for histamine than do H1 and H2 receptors. Activation of H3 receptors also can activate MAP kinase and inhibit the Na+/H+exchanger; activation of H4 receptors mobilizes stored Ca2+ in some cells. Activation of H1 receptors on vascular endothelium stimulates eNOS to produce nitric oxide (NO), which diffuses to nearby smooth muscle cells to increase cyclic GMP and cause relaxation. Stimulation of H1 receptors on smooth muscle will mobilize Ca2+ and cause contraction, whereas activation of H2 receptors on the same smooth muscle cell will link via Gs to enhanced cyclic AMP accumulation, activation of PKA, and thence to relaxation. Pharmacological definition of H1, H2, and H3 receptors is clear because relatively specific agonists and antagonists are available. However, the H4 receptor exhibits 35-40% homology to isoforms of the H3 receptor, and the 2 were harder to distinguish pharmacologically. Several non-imidazole compounds that are more selective H3 antagonists have been developed, and there are now several selective H4 antagonists. 4-Methylhistamine and dimaprit, previously identified as specific H2 agonists, are actually more potent H4 agonists.

H1 AND H2 RECEPTORS. H1 and H2 receptors are distributed widely in the periphery and in the CNS. Histamine causes itching and stimulates secretion from nasal mucosa. It contracts many smooth muscles, such as those of the bronchi and gut, but markedly relaxes others, including those in small blood vessels. Histamine also is a potent stimulus of gastric acid secretion. Other, less prominent effects include formation of edema and stimulation of sensory nerve endings. Bronchoconstriction and contraction of the gut are mediated by H1 receptors. Gastric secretion results from the activation of H2 receptors. Some responses, such as vascular dilation, are mediated by both H1 and H2 receptor stimulation.

H3 AND H4 RECEPTORS. H3 receptors are expressed mainly in the CNS, especially in the basal ganglia, hippocampus, and cortex. H3 receptors function as autoreceptors on histaminergic neurons, inhibiting histamine release and modulating the release of other neurotransmitters. H3 receptors have high constitutive activity and histamine release is tonically inhibited. Inverse agonists thus reduce receptor activation and increase histamine release from histaminergic neurons. H3 agonists promote sleep; thus, H3 antagonists promote wakefulness. H4 receptors primarily are found in eosinophils, dendritic cells, mast cells, monocytes, basophils, and T cells but have also been detected in the GI tract, dermal fibroblasts, CNS, and primary sensory afferent neurons. Activation of H4 receptors has been associated with induction of cellular shape change, chemotaxis, secretion of cytokines, and upregulation of adhesion molecules, suggesting that H4 antagonists may be useful inhibitors of allergic and inflammatory responses.

FEEDBACK REGULATION OF RELEASE. H2 receptor stimulation increases cyclic AMP and leads to feedback inhibition of histamine release from mast cells and basophils, whereas activation of H3 and H4 receptors has the opposite effect by decreasing cellular cyclic AMP. Activation of presynaptic H3 receptors also inhibits histamine release from histaminergic neurons.

CARDIOVASCULAR SYSTEM. Histamine dilates resistance vessels, increases capillary permeability, and lowers systemic blood pressure. In some vascular beds, histamine constricts veins, contributing to the extravasation of fluid and edema formation upstream in capillaries and postcapillary venules.

Vasodilation. This is the most important vascular effect of histamine in humans. H1 receptors have a higher affinity for histamine and cause Ca2+-dependent activation of eNOS in endothelial cells; NO diffuses to vascular smooth muscle, increasing cyclic GMP (see Table 32–1) and causing rapid and short-lived vasodilation. By contrast, activation of H2receptors on vascular smooth muscle stimulates the cyclic AMP–PKA pathway, causing dilation that develops more slowly and is more sustained. As a result, H1 antagonists effectively counter small dilator responses to low concentrations of histamine but only blunt the initial phase of larger responses to higher concentrations of the amine.

Increased “Capillary” Permeability. Histamine’s effect on small vessels results in efflux of plasma protein and fluid into the extracellular spaces and an increase lymph flow, causing edema. H1 receptors on endothelial cells are the major mediators of this response; the role of H2 receptors is uncertain.

Triple Response of Lewis. If histamine is injected intradermally, it elicits a characteristic phenomenon known as the triple response. This consists of:

• A localized “reddening” around the injection site, appearing within a few seconds, maximal ~1 min

• A “flare” or red flushing extending ~1 cm beyond the original red spot and developing more slowly

• A “wheal” or swelling that is discernible in 1-2 min at the injection site

The initial red spot (a few mm) results from the direct vasodilating effect of histamine (H1 receptor–mediated NO production), the flare is due to histamine-induced stimulation of axon reflexes that cause vasodilation indirectly, and the wheal reflects histamine’s capacity to increase capillary permeability (edema formation).

Heart. Histamine affects both cardiac contractility and electrical events directly. It increases the force of contraction of both atrial and ventricular muscle by promoting the influx of Ca2+, and it speeds heart rate by hastening diastolic depolarization in the sinoatrial (SA) node. It also directly slows atrioventricular (AV) conduction to increase automaticity and, in high doses, can elicit arrhythmias. The slowed AV conduction involves mainly H1 receptors, while the other effects are largely attributable to H2 receptors and cyclic AMP accumulation. The direct cardiac effects of histamine given intravenously are overshadowed by baroreceptor reflexes due to reduced blood pressure.

EXTRAVASCULAR SMOOTH MUSCLE. Histamine directly contracts or, more rarely, relaxes various extravascular smooth muscles. Contraction is due to activation of H1receptors on smooth muscle to increase intracellular Ca2+, and relaxation is mainly due to activation of H2 receptors. Although the spasmogenic influence of H1 receptors is dominant in human bronchial muscle, H2 receptors with dilator function also are present. Thus, histamine-induced bronchospasm in vitro is potentiated slightly by H2 blockade.

PERIPHERAL NERVE ENDINGS. Histamine stimulates various nerve endings and sensory effects. In the epidermis, it causes itch; in the dermis, it evokes pain, sometimes accompanied by itching.

HISTAMINE SHOCK. Histamine given in large doses or released during systemic anaphylaxis causes a profound and progressive fall in blood pressure. As the small blood vessels dilate, they trap large amounts of blood, their permeability increases, and plasma escapes from the circulation. Resembling surgical or traumatic shock, these effects diminish effective blood volume, reduce venous return, and greatly lower cardiac output.

HISTAMINE TOXICITY FROM INGESTION. Histamine is the toxin in food poisoning from spoiled scombroid fish such as tuna. Symptoms include severe nausea, vomiting, headache, flushing, and sweating. Histamine toxicity also can follow red wine consumption in persons with a diminished ability to degrade histamine. The symptoms of histamine poisoning can be suppressed by H1 antagonists.

H1 RECEPTOR ANTAGONISTS
PHARMACOLOGICAL PROPERTIES

All the available H1 receptor “antagonists” are actually inverse agonists (see Chapter 3) that reduce constitutive activity of the receptor and compete with histamine. At the tissue level, the effect is proportional to receptor occupancy by the antihistamine. Most H1 antagonists have similar pharmacological actions and therapeutic applications. Their effects are largely predictable from knowledge of the consequences of the activation of H1 receptors by histamine.

Like histamine, many H1 antagonists contain a substituted ethylamine moiety.

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Unlike histamine, which has a primary amino group and a single aromatic ring, most H1 antagonists have a tertiary amino group linked by a 2- or 3-atom chain to 2 aromatic substituents and conform to the general formula

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where Ar is aryl and X is a nitrogen or carbon atom or a —C—O— ether linkage to the β-aminoethyl side chain. Sometimes the 2 aromatic rings are bridged, as in the tricyclic derivatives, or the ethylamine may be part of a ring structure.

EFFECTS ON PHYSIOLOGICAL SYSTEMS

Smooth Muscle. H1 antagonists inhibit both the vasoconstrictor effects of histamine and, to a degree, the more rapid vasodilator effects mediated by activation of H1 receptors on endothelial cells (synthesis/release of NO and other mediators).

Capillary Permeability. H1 antagonists strongly block the increased capillary permeability and formation of edema and wheal caused by histamine.

Flare and Itch. H1 antagonists suppress the action of histamine on nerve endings, including the flare component of the triple response and the itching caused by intradermal injection.

Exocrine Glands. H1 antagonists do not suppress gastric secretion. However, the antimuscarinic properties of many H1 antagonists may contribute to lessened secretion in cholinergically innervated glands and reduce ongoing secretion in, e.g., the respiratory tree.

Immediate Hypersensitivity Reactions: Anaphylaxis and Allergy. During hypersensitivity reactions, histamine is one of the many potent autacoids released and its relative contribution to the ensuing symptoms varies widely with species and tissue. The protection afforded by H1 antagonists thus also varies accordingly. In humans, edema formation and itch are effectively suppressed. Other effects, such as hypotension, are less well antagonized.

CNS. The first-generation H1 antagonists can both stimulate and depress the CNS. Stimulation occasionally is encountered in patients given conventional doses; they become restless, nervous, and unable to sleep. Central excitation also is a striking feature of overdose, which commonly results in convulsions, particularly in infants. Central depression, on the other hand, usually accompanies therapeutic doses of the older H1 antagonists. Diminished alertness, slowed reaction times, and somnolence are common manifestations. Patients vary in their susceptibility and responses to individual drugs. The ethanolamines (e.g., diphenhydramine) are particularly prone to causing sedation. Because of the sedation that occurs with first-generation antihistamines, these drugs cannot be tolerated or used safely by many patients except at bedtime. Even then, patients may experience an antihistamine “hangover” in the morning, resulting in sedation with or without psychomotor impairment. Second-generation “nonsedating” H1 antagonists do not cross the blood-brain barrier appreciably; their sedative effects are similar to those of placebo.

Many antipsychotic agents are H1 and H2 receptor antagonists, but it is unclear whether this property plays a role in the antipsychotic effects of these agents. The atypical antipsychotic agent clozapine is an effective H1 antagonist and a weak H3 antagonist but an H4 receptor agonist in the rat. The H1 antagonist activity of typical and atypical antipsychotic drugs is responsible for the effect of these agents to cause weight gain.

Anticholinergic Effects. Many of the first-generation H1 antagonists tend to inhibit responses to ACh that are mediated by muscarinic receptors and may be manifest during clinical use. Some H1 antagonists also can be used to treat motion sickness (see Chapters 9 and 46), probably as a result of their anticholinergic properties. Indeed, promethazine has perhaps the strongest muscarinic-blocking activity among these agents and is the most effective H1 antagonist in combating motion sickness. The second-generation H1 antagonists have no effect on muscarinic receptors.

Local Anesthetic Effect. Some H1 antagonists have local anesthetic activity, and a few are more potent than procaine. Promethazine (PHENERGAN) is especially active. However, the concentrations required for this effect are much higher than those that antagonize histamine’s interactions with its receptors.

ADME. The H1 antagonists are well absorbed from the GI tract. Following oral administration, peak plasma concentrations are achieved in 2-3 h, and effects usually last 4-6 h; however, some of the drugs are much longer acting (Table 32–2). Diphenhydramine, given orally, reaches a maximal concentration in the blood in ~2 h, remains there for another 2 h, then falls exponentially with a plasma elimination t1/2 of ~4-8 h. The drug is distributed widely throughout the body, including the CNS. Little, if any, is excreted unchanged in the urine; most appears there as metabolites. Peak concentrations of these drugs in the skin may persist after plasma levels have declined. Thus, inhibition of “wheal and flare” responses to the intradermal injection of histamine or allergen can persist for >36 h after treatment, even when the concentration in plasma is low. Like other extensively metabolized drugs, H1antagonists are eliminated more rapidly by children than by adults and more slowly in those with severe liver disease. H1 receptor antagonists also induce hepatic CYPs and thus may facilitate their own metabolism.

Table 32–2

Preparations and Dosage of Representative H1 Receptor Antagonistsa

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The second-generation H1 antagonist loratadine is absorbed rapidly from the GI tract and metabolized in the liver to an active metabolite by CYPs. Consequently, metabolism of loratadine can be affected by other drugs that compete CYPs. Two other second-generation H1 antagonists that were marketed previously, terfenadine and astemizole, also were converted by CYPs to active metabolites. Both of these drugs were found in rare cases to induce a potentially fatal arrhythmia, torsade de pointes, when their metabolism was impaired, such as by liver disease or drugs that inhibit the CYP3A family (see Chapter 29). This led to the withdrawal of terfenadine and astemizole from the market. The active metabolite of terfenadine, fexofenadine, is its replacement. Fexofenadine lacks the toxic side effects of terfenadine, is not sedating, and retains the anti-allergic properties of the parent compound. Another antihistamine developed using this strategy is desloratadine, an active metabolite of loratadine. Cetirizine, loratadine, and fexofenadine are all well absorbed and are excreted mainly in the unmetabolized form. Cetirizine and loratadine are excreted primarily into the urine, whereas fexofenadine is excreted primarily in the feces. Levocetirizine represents the active enantiomer of cetirizine.

THERAPEUTIC USES

H1 antagonists are used for treatment of various immediate hypersensitivity reactions. The central properties of some of the drugs also are of therapeutic value for suppressing motion sickness or for sedation.

ALLERGIC DISEASES. H1 antagonists are useful in acute types of allergy that present with symptoms of rhinitis, urticaria, and conjunctivitis. Their effect is confined to the suppression of symptoms attributable to the histamine released by the antigen-antibody reaction. In bronchial asthma, histamine antagonists have limited efficacy and are not used as sole therapy (see Chapter 36). In the treatment of systemic anaphylaxis, where autacoids other than histamine are important, the mainstay of therapy is epinephrine; histamine antagonists have only a subordinate and adjuvant role. The same is true for severe angioedema, in which laryngeal swelling constitutes a threat to life.

Certain allergic dermatoses respond favorably to H1 antagonists. The benefit is most striking in acute urticaria. Angioedema also responds to treatment with H1 antagonists, but the paramount importance of epinephrine in the severe attack must be reemphasized, especially in life-threatening laryngeal edema (see Chapter 12). H1 antagonists have a place in the treatment of pruritus. Some relief may be obtained in many patients with atopic and contact dermatitis (although topical corticosteroids are more effective) and in such diverse conditions as insect bites and poison ivy. The urticarial and edematous lesions of serum sickness respond to H1 antagonists, but fever and arthralgia often do not.

COMMON COLD. H1 antagonists are without value in combating the common cold. The weak anticholinergic effects of the older agents may tend to lessen rhinorrhea, but this drying effect may do more harm than good, as may their tendency to induce somnolence.

MOTION SICKNESS, VERTIGO, AND SEDATION. Scopolamine, the muscarinic antagonist, given orally, parenterally, or transdermally, is the most effective drug for the prophylaxis and treatment of motion sickness. Some H1 antagonists are useful for milder cases and have fewer adverse effects. These drugs include dimenhydrinate and the piperazines (e.g., cyclizine, meclizine). Promethazine, a phenothiazine, is more potent and more effective; its additional antiemetic properties may be of value in reducing vomiting, but its pronounced sedative action usually is disadvantageous. Whenever possible, the various drugs should be administered ~1 h before the anticipated motion. Treatment after the onset of nausea and vomiting rarely is beneficial. Some H1 antagonists, notably dimenhydrinate and meclizine, often are of benefit in vestibular disturbances such as Meniere disease and in other types of true vertigo. Only promethazine is useful in treating the nausea and vomiting subsequent to chemotherapy or radiation therapy for malignancies; however, other, more effective antiemetic drugs (e.g., 5HT3 antagonists) are available (see Chapter 46). Diphenhydramine can reverse the extrapyramidal side effects caused by phenothiazines (seeChapter 16). The tendency of some H1 receptor antagonists to produce somnolence has led to their use as hypnotics. H1 antagonists, principally diphenhydramine, often are present in various proprietary over-the-counter remedies for insomnia. The sedative and mild antianxiety activities of hydroxyzine contribute to its use as a weak anxiolytic.

ADVERSE EFFECTS. The most frequent side effect in first-generation H1 antagonists is sedation. Concurrent ingestion of alcohol or other CNS depressants produces an additive effect that impairs motor skills. Other untoward central actions include dizziness, tinnitus, lassitude, incoordination, fatigue, blurred vision, diplopia, euphoria, nervousness, insomnia, and tremors. Other side effects include loss of appetite, nausea, vomiting, epigastric distress, and constipation or diarrhea. Taking the drug with meals may reduce their incidence. H1antagonists such as cyproheptadine may increase appetite and cause weight gain. Other side effects, owing to the antimuscarinic actions of some first-generation H1 antagonists, include dryness of the mouth and respiratory passages (sometimes inducing cough), urinary retention or frequency, and dysuria. These effects are not observed with second-generation H1 antagonists.

Allergic dermatitis is not uncommon; other hypersensitivity reactions include drug fever and photosensitization. Hematological complications, such as leukopenia, agranulocytosis, and hemolytic anemia, are very rare. Because H1 antihistamines cross the placenta, caution is advised for women who are or may become pregnant. Several antihistamines (e.g., azelastine, hydroxyzine, fexofenadine) had teratogenic effects in animal studies, whereas others (e.g., chlorpheniramine, diphenhydramine, cetirizine, loratadine) did not. Antihistamines can be excreted in small amounts in breast milk, and first-generation antihistamines taken by lactating mothers may cause symptoms such as irritability, drowsiness, or respiratory depression in the nursing infant.

In acute poisoning with H1 antagonists, their central excitatory effects constitute the greatest danger. The syndrome includes hallucinations, excitement, ataxia, incoordination, athetosis, and convulsions. Fixed, dilated pupils with a flushed face, together with sinus tachycardia, urinary retention, dry mouth, and fever, lend the syndrome a remarkable similarity to that of atropine poisoning. Terminally, there is deepening coma with cardiorespiratory collapse and death usually within 2-18 h. Treatment is along general symptomatic and supportive lines.

Pediatric and Geriatric Indications and Problems. Although little clinical testing has been done, second-generation antihistamines are recommended for elderly patients (>65 years of age), especially those with impaired cognitive function, because of the sedative and anticholinergic effects of first-generation drugs. First-generation antihistamines are not recommended for use in children because their sedative effects can impair learning and school performance. The second-generation drugs have been approved by the FDA for use in children and are available in appropriate lower-dose formulations (e.g., chewable or rapidly dissolving tablets, syrup). Use of over-the-counter cough and cold medicines (containing mixtures of antihistamines, decongestants, antitussives, expectorants) in young children has been associated with serious side effects and deaths. In 2008, the FDA recommended that they not be used in children <2 years of age, and drug manufacturers affiliated with the Consumer Healthcare Products Association voluntarily relabeled products “do not use” for children <4 years of age.

AVAILABLE H1 ANTAGONISTS. Summarized below are the therapeutic side effects of a number of H1 antagonists, grouped by their chemical structures. Representative preparations are listed in Table 32–2.

Dibenzoxepin Tricyclics (Doxepin). Doxepin, the only drug in this class, is marketed as a tricyclic antidepressant (see Chapter 16). It also is one of the most potent H1 antagonists and has significant H2 antagonist activity, but this does not translate into greater clinical effectiveness. It can cause drowsiness and is associated with anticholinergic effects. Doxepin is better tolerated by patients with depression than those who are not depressed, where even small doses (e.g., 20 mg) may cause disorientation and confusion.

Ethanolamines (Prototype: Diphenhydramine). These drugs possess significant antimuscarinic activity and have a pronounced tendency to induce sedation. About half of those treated acutely with conventional doses experience somnolence. The incidence of GI side effects, however, is low with this group.

Ethylenediamines (Prototype: Pyrilamine). These include some of the most specific H1 antagonists. Although their central effects are relatively feeble, somnolence occurs in a fair proportion of patients. GI side effects are quite common.

Alkylamines (Prototype: Chlorpheniramine). These are among the most potent H1 antagonists. The drugs are less prone to produce drowsiness and are more suitable for daytime use, but a significant proportion of patients do experience sedation. Side effects involving CNS stimulation are more common than with other groups.

First-Generation Piperazines. The oldest member of this group, chlorcyclizine, has a more prolonged action and produces a comparatively low incidence of drowsiness. Hydroxyzine is a long-acting compound that is used widely for skin allergies; its considerable CNS-depressant activity may contribute to its prominent anti-pruritic action. Cyclizine and meclizine have been used primarily to counter motion sickness, although promethazine and diphenhydramine are more effective (as is the antimuscarinic scopolamine).

Second-Generation Piperazines (Cetirizine). Cetirizine is the only drug in this class. It has minimal anticholinergic effects. It also has negligible penetration into the brain but is associated with a somewhat higher incidence of drowsiness than the other second-generation H1 antagonists. The active enantiomer levocetirizine has slightly greater potency and may be used at half the dose with less resultant sedation.

Phenothiazines (Prototype: Promethazine). Most drugs of this class are H1 antagonists and also possess considerable anticholinergic activity. Promethazine, which has prominent sedative effects, and its many congeners are used primarily for their antiemetic effects (see Chapter 46).

First-Generation Piperidines (Cyproheptadine, Phenindamine). Cyproheptadine uniquely has both antihistamine and anti-serotonin activity. Cyproheptadine and phenindamine cause drowsiness and also have significant anticholinergic effects and can increase appetite.

Second-Generation Piperidines (Prototype: Terfenadine). Terfenadine and astemizole were withdrawn from the market. Current drugs in this class include loratadine, desloratadine, and fexofenadine. These agents are highly selective for H1 receptors, lack significant anticholinergic actions, and penetrate poorly into the CNS. Taken together, these properties appear to account for the low incidence of side effects of piperidine antihistamines.

H2 RECEPTOR ANTAGONISTS

The pharmacology and clinical utility of H2 antagonists to inhibit gastric acid secretion are described in Chapter 45.

H3 RECEPTOR AND LIGANDS

H3 receptors are presynaptic autoreceptors on histaminergic neurons that originate in the tuberomammillary nucleus in the hypothalamus and project throughout the CNS, most prominently to the hippocampus, amygdala, nucleus accumbens, globus pallidus, striatum, hypothalamus, and cortex. The activated H3 receptor depresses neuronal firing at the level of cell bodies/dendrites and decreases histamine release from depolarized terminals. Thus, H3 agonists decrease histaminergic transmission, and antagonists increase it.

H3 receptors also are presynaptic heteroreceptors on a variety of neurons in brain and peripheral tissues, and their activation inhibits release from noradrenergic, serotoninergic, GABA-ergic, cholinergic, and glutamatergic neurons, as well as pain-sensitive C fibers. H3 receptors in the brain have significant constitutive activity in the absence of agonist; consequently, inverse agonists will activate these neurons.

H3 antagonists/inverse agonists have a wide range of central effects; for example, they promote wakefulness, improve cognitive function (e.g., enhance memory, learning, and attention), and reduce food intake. As a result, there is considerable interest in developing H3 antagonists for possible treatment of sleeping disorders, attention deficit hyperactivity disorder (ADHD), epilepsy, cognitive impairment, schizophrenia, obesity, neuropathic pain, and Alzheimer disease. Thioperamide was the first “specific” H3 antagonist/inverse agonist available experimentally, but was equally effective at the H4 receptor. A number of other imidazole derivatives have been developed as H3 antagonists, including clobenpropit, ciproxifan, and proxyfan. More selective non-imidazole H3 antagonists/inverse agonists are in phase II clinical trials.

H4 RECEPTOR AND LIGANDS

H4 receptors are expressed on cells with inflammatory or immune functions and can mediate histamine-induced chemotaxis, induction of cell shape change, secretion of cytokines, and upregulation of adhesion molecules. The H4 receptors also have a role in pruritus and neuropathic pain. Because of the unique localization and function of H4 receptors, H4antagonists are promising candidates to treat these conditions. No H4 antagonists have yet been tested in clinical trials.

The H4 receptor has the highest homology with the H3 receptor and binds many H3 ligands, especially those with imidazole rings, although sometimes with different effects. For example, thioperamide is an effective inverse agonist at both H3 and H4 receptors, whereas H3 inverse agonist clobenpropit is a partial agonist of the H4 receptor; impentamine (an H3agonist) and iodophenpropit (an H3 inverse agonist) are both neutral H4 antagonists.

BRADYKININ, KALLIDIN, AND THEIR ANTAGONISTS

Tissue damage, allergic reactions, viral infections, and other inflammatory events activate a series of proteolytic reactions that generate bradykinin and kallidin in tissues. These peptides contribute to inflammatory responses as autacoids that act locally to produce pain, vasodilation, and increased vascular permeability but can also have beneficial effects, for example in the heart, kidney, and circulation. Much of their activity is due to stimulation of the release of potent mediators such as prostaglandins, NO, or endothelium-derived hyperpolarizing factor (EDHF).

THE ENDOGENOUS KALLIKREIN–KININOGEN–KININ SYSTEM

Bradykinin is a nonapeptide. Kallidin is a decapeptide containing an additional N-terminal lysine, is sometimes referred to as lysyl-bradykinin (Table 32–3). The 2 peptides are cleaved from 32 globulins termed kininogens (Figure 32–2). There are 2 kininogens: high-molecular-weight (HMW) kininogen and low-molecular-weight (LMW) kininogen. A number of serine proteases will generate kinins, but the highly specific proteases that release bradykinin and kallidin from the kininogens are termed kallikreins.

Table 32–3

Structure of Kinin Agonists and Antagonists

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Figure 32–2 Synthesis and signaling in the kallikrein-kinin and renin-angiotensin systems. Bradykinin is generated by the action of plasma kallikrein on high-molecular-weight (HMW) kininogen and kallidin is released by the hydrolysis of low-molecular-weight (LMW) kininogen by tissue kallikrein. Kallidin and bradykinin are the natural ligands of the B2 receptor but can be converted to corresponding agonists of the B1 receptor by removal of the C-terminal Arg by kininase I–type enzymes: the plasma membrane–bound carboxypeptidase M (CPM) or soluble plasma carboxypeptidase N (CPN). Kallidin or [des-Arg10]-kallidin can be converted to the active peptides bradykinin or to [des-Arg9]-bradykinin by aminopeptidase cleavage of the N-terminal Lys residue. In a parallel fashion, angiotensin I is generated by the action of renin on angiotensinogen. Angiotensin I is then converted by angiotensin-converting enzyme (ACE) to the active peptide angiotensin II (AngII). These 2 systems have opposing effects. Bradykinin is a vasodilator that stimulates Na+ excretion by activating the B2 receptor. AngII is a potent vasoconstrictor that also causes aldosterone release and Na+ retention via activation of the AT1 receptor. ACE simultaneously generates active AngII and inactivates bradykinin and kallidin; thus, its effects are prohypertensive, and ACE inhibitors are effective antihypertensive agents.

KALLIKREINS. Bradykinin and kallidin are cleaved from HMW or LMW kininogens by plasma and tissue kallikrein, respectively (see Figure 32–2). Plasma kallikrein and tissue kallikrein are distinct enzymes that are activated by different mechanisms. Plasma prekallikrein is an inactive protein of ~88,000 Da that complexes with its substrate, HMW kininogen. The ensuing proteolytic cascade is restrained by the protease inhibitors present in plasma. Among the most important of these are the inhibitor of the activated first component of complement (C1-INH) and r2 macroglobulin. Under experimental conditions, the kallikrein–kinin system is activated by the binding of factor XII, also known asHageman factor, to negatively charged surfaces. Factor XII, a protease that is common to both the kinin and the intrinsic coagulation cascades (see Chapter 30), undergoes autoactivation and, in turn, activates prekallikrein. Importantly, kallikrein further activates factor XII, thereby exerting a positive feedback on the system. Tissue kallikrein (29,000 Da) is synthesized as a preproprotein in the epithelial cells or secretory cells in several tissues, including salivary glands, pancreas, prostate, and distal nephron. Tissue kallikrein also is expressed in human neutrophils. It acts locally near its sites of origin. The synthesis of tissue prokallikrein is controlled by a number of factors, including aldosterone in the kidney and salivary gland and androgens in certain other glands. The activation of tissue prokallikrein to kallikrein requires proteolytic cleavage to remove a 7–amino acid propeptide.

KININOGENS. The 2 substrates for the kallikreins, HMW kininogen and LMW kininogen, are derived from a single gene by alternative splicing. HMW kininogen is cleaved by plasma and tissue kallikrein to yield bradykinin and kallidin, respectively. LMW kininogen is a substrate only of tissue kallikrein, and the product is kallidin.

METABOLISM OF KININS. The decapeptide kallidin is about as active as the nonapeptide bradykinin, even without conversion to bradykinin, which occurs when the N-terminal lysine residue is removed by an aminopeptidase (see Figure 32–2). The t1/2 of kinins in plasma is only ~15 sec; 80-90% of the kinins may be destroyed in a single passage through the pulmonary vascular bed. Plasma concentrations of bradykinin are difficult to measure because inadequate inhibition of kininogenases or kininases in the blood can lead to artifactual formation or degradation of bradykinin during blood collection. When care is taken to inhibit these processes, the reported physiological concentrations of bradykinin in blood are in the picomolar range.

The principal catabolizing enzyme in the lung and other vascular beds is kininase II, or ACE (see Chapter 26). Removal of the C-terminal dipeptide by ACE or neutral endopeptidase 24.11 (neprilysin) inactivates kinins (Figure 32–3). A slower-acting enzyme, carboxypeptidase N (lysine carboxypeptidase, kininase I), releases the C-terminal arginine residue, producing [desArg9]-bradykinin or [des-Arg10]-kallidin (see Table 32–3 and Figures 32–2 and 32–3), which are potent B1 receptor agonists. Carboxypeptidase N is expressed constitutively in blood plasma. A familial carboxypeptidase N deficiency is associated with angioedema or urticaria. Carboxypeptidase M, which also cleaves basic C-terminal amino acids, is a widely distributed plasma membrane–bound enzyme. Finally, aminopeptidase P can cleave the N-terminal arginine, rendering bradykinin inactive and susceptible to cleavage by dipeptidyl peptidase IV.

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Figure 32–3 Degradation of bradykinin.

KININ RECEPTORS. The B1 and B2 kinin receptors are GPCRs.

The bradykinin B2 receptor is expressed in most normal tissues, where it selectively binds intact bradykinin and kallidin (see Table 32–3 and see Figure 32–2). The B2 receptor mediates most of bradykinin’s effects under normal circumstances, whereas synthesis of the B1 receptor is induced by inflammatory mediators in inflammatory conditions. Both B1and B2 receptors couple through Gq to activate PLC and increase intracellular Ca2+; the physiological response depends on receptor distribution on particular cell types and occupancy by agonist peptides. For example, on endothelial cells, activation of B2 receptors results in Ca2+–calmodulin–dependent activation of eNOS and generation of NO, which causes cyclic GMP accumulation and relaxation in neighboring smooth muscle cells. However, in endothelial cells under inflammatory conditions, B1 receptor stimulation results in prolonged NO production via Gi and MAP kinase-dependent activation of iNOS expression. On smooth muscle cells, activation of kinin receptors coupling through Gq results in an increased [Ca2+]i and contraction. Bradykinin activates the pro-inflammatory transcription factor NF- B through GBq and subunits and also activates the MAP kinase pathway. B1 and B2 receptors also can couple through Gi to activate PLA2, causing the release of arachidonic acid and the local generation of a variety of metabolites, including inflammatory mediators and vasodilator epoxyeicosatrienoic acids (EETs) and prostacyclin such as EDHF. Kallikrein also plays a role in the intrinsic blood coagulation pathway.

The B1 receptor is activated by the des-Arg metabolites of bradykinin and kallidin produced by the actions of carboxypeptidases N and M (see Table 32–3). Interestingly, carboxypeptidase M and the B1 receptor interact on the cell surface to form an efficient signaling complex. B1 receptors are normally absent or expressed at low levels in most tissues. B1 receptor expression is upregulated by tissue injury and inflammation and by cytokines, endotoxins, and growth factors. Carboxypeptidase M expression also is increased by cytokines, to such a degree that B1 receptor effects may predominate over B2 effects. The B1 and B2 receptors differ in their time courses of downregulation; the B2 receptor response is rapidly desensitized, whereas the B1 response is not. This likely is due to modification at a Ser/Thr-rich cluster present in the C-terminal tail of the B2 receptor that is not conserved in the B1 receptor sequence.

FUNCTIONS AND PHARMACOLOGY OF KALLIKREINS AND KININS

The utility of specific kinin-receptor antagonists currently is being investigated in diverse areas such as pain, inflammation, chronic inflammatory diseases, and the cardiovascular system. That the beneficial effects of ACE inhibitor therapy rests in part on enhancing bradykinin activity (e.g., on the heart, kidney, blood pressure; see Chapter 26) demonstrates the complexities in interpreting bradykinin’s actions.

Pain. The kinins are powerful algesic agents that cause an intense burning pain when applied to the exposed base of a blister. Bradykinin excites primary sensory neurons and provokes the release of neuropeptides such as substance P, neurokinin A, and calcitonin gene–related peptide. Although there is overlap, B2 receptors generally mediate acute bradykinin algesia, whereas the pain of chronic inflammation appears to involve increased numbers and activation of B1 receptors.

Inflammation. Kinins participate in a variety of inflammatory conditions. Plasma kinins increase permeability in the microcirculation, acting on the small venules to cause disruption of the inter-endothelial junctions. This, together with an increased hydrostatic pressure gradient, causes edema. Edema, coupled with stimulation of nerve endings, results in a “wheal and flare” response to intradermal injection. In hereditary angioedema, bradykinin is formed, and there is depletion of the upstream components of the kinin cascade during episodes of swelling, laryngeal edema, and abdominal pain. B1 receptors on inflammatory cells (e.g., macrophages) can elicit production of the inflammatory mediators IL-1 and TNF-α. Kinin levels are increased in a number of chronic inflammatory diseases and may be significant in gout, disseminated intravascular coagulation, inflammatory bowel disease, rheumatoid arthritis, or asthma. Kinins also may contribute to the skeletal changes seen in chronic inflammatory states. Kinins stimulate bone resorption through B1 and possibly B2 receptors, perhaps by osteoblast-mediated osteoclast activation (see Chapter 44).

Respiratory Disease. The kinins have been implicated in allergic airway disorders such as asthma and rhinitis. Inhalation or intravenous injection of kinins causes bronchospasm in asthmatic patients but not in normal individuals. This bradykinin-induced bronchoconstriction is blocked by anticholinergic agents but not by antihistamines or cyclooxygenase inhibitors. Similarly, nasal challenge with bradykinin is followed by sneezing and glandular secretions in patients with allergic rhinitis.

Cardiovascular System. Infusion of bradykinin causes vasodilation and lowers blood pressure. Bradykinin causes vasodilation by activating its B2 receptor on endothelial cells, resulting in the generation of NO, prostacyclin, and a hyperpolarizing EET that is a CYP-derived metabolite of arachidonic acid. The endogenous kallikrein–kinin system plays a minor role in the regulation of normal blood pressure, but it may be important in hypertensive states. Urinary kallikrein concentrations are decreased in individuals with high blood pressure.

The kallikrein–kinin system is cardioprotective. Many of the beneficial effects of ACE inhibitors on heart function are attributable to enhancement of bradykinin effects, such as their antiproliferative activity or ability to increase glucose uptake in tissue. Bradykinin contributes to the beneficial effect of preconditioning to protect the heart against ischemia and reperfusion injury. Bradykinin also stimulates tissue plasminogen activator (tPA) release from the vascular endothelium and may contribute to the endogenous defense against some cardiovascular events, such as myocardial infarction and stroke.

Kidney. Renal kinins act in a paracrine manner to regulate urine volume and composition. Kallikrein is synthesized and secreted by the connecting cells of the distal nephron. Tissue kininogen and kinin receptors are present in the cells of the collecting duct. Like other vasodilators, kinins increase renal blood flow. Bradykinin also causes natriuresis by inhibiting sodium reabsorption at the cortical collecting duct. Treatment with mineralocorticoids, ACE inhibitors, and neutral endopeptidase (neprilysin) inhibitors increases renal kallikrein.

Other Effects. Kinins promote dilation of the fetal pulmonary artery, closure of the ductus arteriosus, and constriction of the umbilical vessels, all of which occur in the transition from fetal to neonatal circulation. Kinins also affect the CNS, disrupting the blood-brain barrier and allowing increased CNS penetration.

Potential Therapeutic Uses. Bradykinin contributes to many of the effects of the ACE inhibitors. Aprotinin, a kallikrein and plasmin inhibitor, has been administered to patients undergoing coronary bypass to minimize bleeding and blood requirements. Based on the pro-inflammatory and algesic effects of kinins, B1 and B2 receptor antagonists are being tested for the treatment of inflammatory conditions and certain types of pain.

KALLIKREIN INHIBITORS

Aprotinin (TRASYLOL) is a natural proteinase inhibitor that inhibits mediators of the inflammatory response, fibrinolysis, and thrombin generation following cardiopulmonary bypass surgery, including kallikrein and plasmin. Aprotinin has been employed clinically to reduce blood loss in patients undergoing coronary artery bypass surgery, but unfavorable survival statistics in retrospective and prospective studies have resulted in its discontinuation. Ecallantide (DX-88), a synthetic plasma kallikrein inhibitor, inhibits acute episodes of angioedema in patients with hereditary angioedema.

BRADYKININ AND THE EFFECTS OF ACE INHIBITORS. ACE inhibitors, widely used in the treatment of hypertension, congestive heart failure, and diabetic nephropathy, block the conversion of AngI to AngII and also block the degradation of bradykinin by ACE (see Figure 32–2 and Chapter 26). Numerous studies demonstrate that bradykinin contributes to many of the protective effects of ACE inhibitors. The search is on to find a suitable stable B2 agonist for clinical evaluation that provides cardiovascular benefit without pro-inflammatory effects.

A rare side effect of ACE inhibitors is angioedema, which may be connected to the inhibition of kinin metabolism by ACE. A common side effect of ACE inhibitors is a chronic, nonproductive cough that dissipates when the drug is stopped. Bradykinin may contribute to the effects of the AT1-receptor antagonists. During AT1 receptor blockade, AngII concentrations increase, which enhances signaling through the unopposed AT2 subtype receptor, causing an increase in renal bradykinin concentrations.

KININ RECEPTOR ANTAGONISTS. The selective B2 receptor antagonist HOE-140 (icatibant; FIRAZYR) has been approved in the E.U. and recently in the U.S. for treatment of acute episodes of swelling in patients with hereditary angioedema. It is administered by subcutaneous injection.