Basic and Clinical Pharmacology, 13th Ed.

Histamine, Serotonin, & the Ergot Alkaloids

Bertram G. Katzung, MD, PhD

CASE STUDY

A healthy 45-year-old physician attending a reunion in a vacation hotel developed dizziness, redness of the skin over the head and chest, and tachycardia while eating. A short time later, another physician at the table developed similar signs and symptoms with marked orthostatic hypotension. The menu included a green salad, sauteed fish with rice, and apple pie. What is the probable diagnosis? How would you treat these patients?

It has long been known that many tissues contain substances that, when released by various stimuli, cause physiologic effects such as reddening of the skin, pain or itching, and bronchospasm. Later, it was discovered that many of these substances are also present in nervous tissue and have multiple functions. Histamine and serotonin (5-hydroxytryptamine, 5-HT) are biologically active amines that function as neurotransmitters and are found in non-neural tissues, have complex physiologic and pathologic effects through multiple receptor subtypes, and are often released locally. Together with endogenous peptides (see Chapter 17), prostaglandins and leukotrienes (see Chapter 18), and cytokines (see Chapter 55), they constitute the autacoid group of drugs.

Because of their broad and largely undesirable peripheral effects, neither histamine nor serotonin has any clinical application in the treatment of disease. However, compounds that selectively activate certain receptor subtypes or selectively antagonize the actions of these amines are of considerable clinical value. This chapter therefore emphasizes the basic pharmacology of the agonist amines and the clinical pharmacology of the more selective agonist and antagonist drugs. The ergot alkaloids, compounds with partial agonist activity at serotonin and several other receptors, are discussed at the end of the chapter.

image HISTAMINE

Histamine was synthesized in 1907 and later isolated from mammalian tissues. Early hypotheses concerning the possible physiologic roles of tissue histamine were based on similarities between the effects of intravenously administered histamine and the symptoms of anaphylactic shock and tissue injury. Marked species variation is observed, but in humans histamine is an important mediator of immediate allergic (such as urticaria) and inflammatory reactions, although it plays only a modest role in anaphylaxis. Histamine plays an important role in gastric acid secretion (see Chapter 62) and functions as a neurotransmitter and neuromodulator (see Chapters 6 and 21). Newer evidence indicates that histamine also plays a role in immune functions and chemotaxis of white blood cells.

BASIC PHARMACOLOGY OF HISTAMINE

Chemistry & Pharmacokinetics

Histamine occurs in plants as well as in animal tissues and is a component of some venoms and stinging secretions.

Histamine is formed by decarboxylation of the amino acid L-histidine, a reaction catalyzed in mammalian tissues by the enzyme histidine decarboxylase. Once formed, histamine is either stored or rapidly inactivated. Very little histamine is excreted unchanged. The major metabolic pathways involve conversion to N-methylhistamine, methylimidazoleacetic acid, and imidazoleacetic acid (IAA). Certain neoplasms (systemic mastocytosis, urticaria pigmentosa, gastric carcinoid, and occasionally myelogenous leukemia) are associated with increased numbers of mast cells or basophils and with increased excretion of histamine and its metabolites.

image

Most tissue histamine is sequestered and bound in granules (vesicles) in mast cells or basophils; the histamine content of many tissues is directly related to their mast cell content. The bound form of histamine is biologically inactive, but as noted below, many stimuli can trigger the release of mast cell histamine, allowing the free amine to exert its actions on surrounding tissues. Mast cells are especially rich at sites of potential tissue injury—nose, mouth, and feet; internal body surfaces; and blood vessels, particularly at pressure points and bifurcations.

Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. Strong evidence implicates endogenous neurotransmitter histamine in many brain functions such as neuroendocrine control, cardiovascular regulation, thermal and body weight regulation, and sleep and arousal (see Chapter 21).

A second important nonneuronal site of histamine storage and release is the enterochromaffin-like (ECL) cells of the fundus of the stomach. ECL cells release histamine, one of the primary gastric acid secretagogues, to activate the acid-producing parietal cells of the mucosa (see Chapter 62).

Storage & Release of Histamine

The stores of histamine in mast cells can be released through several mechanisms.

A. Immunologic Release

Immunologic processes account for the most important pathophysiologic mechanism of mast cell and basophil histamine release. These cells, if sensitized by IgE antibodies attached to their surface membranes, degranulate explosively when exposed to the appropriate antigen (see Figure 55–5, effector phase). This type of release also requires energy and calcium. Degranulation leads to the simultaneous release of histamine, adenosine triphosphate (ATP), and other mediators that are stored together in the granules. Histamine released by this mechanism is a mediator in immediate (type I) allergic reactions, such as hay fever and acute urticaria. Substances released during IgG- or IgM-mediated immune reactions that activate the complement cascade also release histamine from mast cells and basophils.

By a negative feedback control mechanism mediated by H2 receptors, histamine appears to modulate its own release and that of other mediators from sensitized mast cells in some tissues. In humans, mast cells in skin and basophils show this negative feedback mechanism; lung mast cells do not. Thus, histamine may act to limit the intensity of the allergic reaction in the skin and blood.

Endogenous histamine has a modulating role in a variety of inflammatory and immune responses. Upon injury to a tissue, released histamine causes local vasodilation and leakage of plasma-containing mediators of acute inflammation (complement, C-reactive protein) and antibodies. Histamine has an active chemotactic attraction for inflammatory cells (neutrophils, eosinophils, basophils, monocytes, and lymphocytes). Histamine inhibits the release of lysosome contents and several T- and B-lymphocyte functions. Most of these actions are mediated by H2 or H4 receptors. Release of peptides from nerves in response to inflammation is also probably modulated by histamine acting on presynaptic H3 receptors.

B. Chemical and Mechanical Release

Certain amines, including drugs such as morphine and tubocurarine, can displace histamine from its bound form within cells. This type of release does not require energy and is not associated with mast cell injury or degranulation. Loss of granules from the mast cell also releases histamine, because sodium ions in the extracellular fluid rapidly displace the amine from the complex. Chemical and mechanical mast cell injury causes degranulation and histamine release. Compound 48/80, an experimental drug, selectively releases histamine from tissue mast cells by an exocytotic degranulation process requiring energy and calcium.

Pharmacodynamics

A. Mechanism of Action

Histamine exerts its biologic actions by combining with specific receptors located on the cell membrane. Four different histamine receptors have been characterized and are designated H1–H4; they are described in Table 16–1. Unlike the other amine transmitter receptors discussed previously, no subfamilies have been found within these major types, although different splice variants of several receptor types have been described.

TABLE 16–1 Histamine receptor subtypes.

image

All four receptor types have been cloned and belong to the large superfamily of G-protein-coupled receptors (GPCR). The structures of the H1 and H2 receptors differ significantly and appear to be more closely related to muscarinic and 5-HT1 receptors, respectively, than to each other. The H4 receptor has about 40% homology with the H3 receptor but does not seem to be closely related to any other histamine receptor. All four histamine receptors have been shown to have constitutive activity in some systems; thus, some antihistamines previously considered to be traditional pharmacologic antagonists must now be considered to be inverse agonists (see Chapters 1 and 2). Indeed, many first- and second-generation H1 blockers function as inverse agonists. Furthermore, a single molecule may be an agonist at one histamine receptor and an antagonist or inverse agonist at another. For example, clobenpropit, an agonist at H4 receptors, is an antagonist or inverse agonist at H3 receptors (Table 16–1).

In the brain, H1 and H2 receptors are located on postsynaptic membranes, whereas H3 receptors are predominantly presynaptic. Activation of H1 receptors, which are present in endothelium, smooth muscle cells, and nerve endings, usually elicits an increase in phosphoinositol hydrolysis and an increase in inositol trisphosphate (IP3) and intracellular calcium. Activation of H2 receptors, present in gastric mucosa, cardiac muscle cells, and some immune cells, increases intracellular cyclic adenosine monophosphate (cAMP) via Gs. Like the β2 adrenoceptor, under certain circumstances the H2 receptor may couple to Gq, activating the IP3-DAG (inositol 1,4,5-trisphosphate-diacylglycerol) cascade. Activation of H3 receptors decreases transmitter release from histaminergic and other neurons, probably mediated by a decrease in calcium influx through N-type calcium channels in nerve endings. H4receptors are found mainly on leukocytes in the bone marrow and circulating blood. H4 receptors appear to have very important chemotactic effects on eosinophils and mast cells. In this role, they seem to play a part in inflammation and allergy. They may also modulate production of these cell types and they may mediate, in part, the previously recognized effects of histamine on cytokine production.

B. Tissue and Organ System Effects of Histamine

Histamine exerts powerful effects on smooth and cardiac muscle, on certain endothelial and nerve cells, on the secretory cells of the stomach, and on inflammatory cells. However, sensitivity to histamine varies greatly among species. Guinea pigs are exquisitely sensitive; humans, dogs, and cats somewhat less so; and mice and rats very much less so.

1.Nervous system—Histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itching. This H1-mediated effect is an important component of the urticarial response and reactions to insect and nettle stings. Some evidence suggests that local high concentrations can also depolarize efferent (axonal) nerve endings (see Triple Response, item 8 in this list). In the mouse, and probably in humans, respiratory neurons signaling inspiration and expiration are modulated by H1 receptors. H1 and H3 receptors play important roles in appetite and satiety; antipsychotic drugs that block these receptors cause significant weight gain (see Chapter 29). These receptors may also participate in nociception. Presynaptic H3 receptors play important roles in modulating release of several transmitters in the nervous system. H3 agonists reduce the release of acetylcholine, amine, and peptide transmitters in various areas of the brain and in peripheral nerves. An investigational inverse H3 agonist, pitolisant(BF2649), appears to reduce drowsiness in patients with narcolepsy.

2.Cardiovascular system—In humans, injection or infusion of histamine causes a decrease in systolic and diastolic blood pressure and an increase in heart rate. The blood pressure changes are caused by the direct vasodilator action of histamine on arterioles and precapillary sphincters; the increase in heart rate involves both stimulatory actions of histamine on the heart and a reflex tachycardia. Flushing, a sense of warmth, and headache may also occur during histamine administration, consistent with the vasodilation. Vasodilation elicited by small doses of histamine is caused by H1-receptor activation and is mediated mainly by release of nitric oxide from the endothelium (see Chapter 19). The decrease in blood pressure is usually accompanied by a reflex tachycardia. Higher doses of histamine activate the H2-mediated cAMP process of vasodilation and direct cardiac stimulation. In humans, the cardiovascular effects of small doses of histamine can usually be antagonized by H1-receptor antagonists alone.

Histamine-induced edema results from the action of the amine on H1 receptors in the vessels of the microcirculation, especially the postcapillary vessels. The effect is associated with the separation of the endothelial cells, which permits the transudation of fluid and molecules as large as small proteins into the perivascular tissue. This effect is responsible for urticaria (hives), which signals the release of histamine in the skin. Studies of endothelial cells suggest that actin and myosin within these cells cause contraction, resulting in separation of the endothelial cells and increased permeability.

Direct cardiac effects of histamine include both increased contractility and increased pacemaker rate. These effects are mediated chiefly by H2 receptors. In human atrial muscle, histamine can also decrease contractility; this effect is mediated by H1 receptors. The physiologic significance of these cardiac actions is not clear. Some of the cardiovascular signs and symptoms of anaphylaxis are due to released histamine, although several other mediators are involved and are much more important than histamine in humans.

3.Bronchiolar smooth muscle—In both humans and guinea pigs, histamine causes bronchoconstriction mediated by H1 receptors. In the guinea pig, this effect is the cause of death from histamine toxicity, but in humans with normal airways, bronchoconstriction following small doses of histamine is not marked. However, patients with asthma are very sensitive to histamine. The bronchoconstriction induced in these patients probably represents a hyperactive neural response, since such patients also respond excessively to many other stimuli, and the response to histamine can be blocked by autonomic blocking drugs such as ganglion blocking agents as well as by H1-receptor antagonists (see Chapter 20). Although methacholine provocation is more commonly used, tests using small doses of inhaled histamine have been used in the diagnosis of bronchial hyperreactivity in patients with suspected asthma or cystic fibrosis. Such individuals may be 100 to 1000 times more sensitive to histamine (and methacholine) than are normal subjects. Curiously, a few species (eg, rabbit) respond to histamine with bronchodilation, reflecting the dominance of the H2 receptor in their airways.

4.Gastrointestinal tract smooth muscle—Histamine causes contraction of intestinal smooth muscle, and histamine-induced contraction of guinea pig ileum is a standard bioassay for this amine. The human gut is not as sensitive as that of the guinea pig, but large doses of histamine may cause diarrhea, partly as a result of this effect. This action of histamine is mediated by H1 receptors.

5.Other smooth muscle organs—In humans, histamine generally has insignificant effects on the smooth muscle of the eye and genitourinary tract. However, pregnant women suffering anaphylactic reactions may abort as a result of histamine-induced contractions, and in some species the sensitivity of the uterus is sufficient to form the basis for a bioassay.

6.Secretory tissue—Histamine has long been recognized as a powerful stimulant of gastric acid secretion and, to a lesser extent, of gastric pepsin and intrinsic factor production. The effect is caused by activation of H2 receptors on gastric parietal cells and is associated with increased adenylyl cyclase activity, cAMP concentration, and intracellular Ca2+ concentration. Other stimulants of gastric acid secretion such as acetylcholine and gastrin do not increase cAMP even though their maximal effects on acid output can be reduced—but not abolished—by H2-receptor antagonists. These actions are discussed in more detail in Chapter 62. Histamine also stimulates secretion in the small and large intestine. In contrast, H3-selective histamine agonists inhibit acid secretion stimulated by food or pentagastrin in several species.

Histamine has much smaller effects on the activity of other glandular tissue at ordinary concentrations. Very high concentrations can cause catecholamine release from the adrenal medulla.

7.Metabolic effects—Recent studies of H3-receptor knockout mice demonstrate that absence of this receptor results in increased food intake, decreased energy expenditure, and obesity. They also show insulin resistance and increased blood levels of leptin and insulin. It is not yet known whether the H3 receptor has a similar role in humans, but research is underway to determine whether H3 agonists are useful in the treatment of obesity.

8.The “triple response”—Intradermal injection of histamine causes a characteristic red spot, edema, and flare response. The effect involves three separate cell types: smooth muscle in the microcirculation, capillary or venular endothelium, and sensory nerve endings. At the site of injection, a reddening appears owing to dilation of small vessels, followed soon by an edematous wheal at the injection site and a red irregular flare surrounding the wheal. The flare is said to be caused by an axon reflex. A sensation of itching may accompany these effects.

Similar local effects may be produced by injecting histamine liberators (compound 48/80, morphine, etc) intradermally or by applying the appropriate antigens to the skin of a sensitized person. Although most of these local effects can be prevented by adequate doses of an H1-receptor-blocking agent, H2 and H3 receptors may also be involved.

9.Other effects possibly mediated by histamine receptors—In addition to the local stimulation of peripheral pain nerve endings via H3 and H1 receptors, histamine may play a role in nociception in the central nervous system. Burimamide, an early candidate for H2-blocking action, and newer analogs with no notable effect on H1, H2, or H3 receptors, have been shown to have significant analgesic action in rodents when administered into the central nervous system. The analgesia is said to be comparable to that produced by opioids, but tolerance, respiratory depression, and constipation have not been reported.

Other Histamine Agonists

Small substitutions on the imidazole ring of histamine significantly modify the selectivity of the compounds for the histamine receptor subtypes. Some of these are listed in Table 16–1.

CLINICAL PHARMACOLOGY OF HISTAMINE

Clinical Uses

In pulmonary function laboratories, histamine aerosol has been used as a provocative test of bronchial hyperreactivity. Histamine has no other current clinical applications.

Toxicity & Contraindications

Adverse effects of histamine release, like those following administration of histamine, are dose related. Flushing, hypotension, tachycardia, headache, urticaria, bronchoconstriction, and gastrointestinal upset are noted. These effects are also observed after the ingestion of spoiled fish (scombroid fish poisoning), and histamine produced by bacterial action in the flesh of improperly stored fish is the major causative agent.

Histamine should not be given to patients with asthma (except as part of a carefully monitored test of pulmonary function) or to patients with active ulcer disease or gastrointestinal bleeding.

HISTAMINE ANTAGONISTS

The effects of histamine released in the body can be reduced in several ways. Physiologic antagonists, especially epinephrine, have smooth muscle actions opposite to those of histamine, but they act at different receptors. This is important clinically because injection of epinephrine can be lifesaving in systemic anaphylaxis and in other conditions in which massive release of histamine—and other more important mediators—occurs.

Release inhibitors reduce the degranulation of mast cells that results from immunologic triggering by antigen-IgE interaction. Cromolyn and nedocromil appear to have this effect (see Chapter 20) and have been used in the treatment of asthma. Beta2-adrenoceptor agonists also appear capable of reducing histamine release.

Histamine receptor antagonists represent a third approach to the reduction of histamine-mediated responses. For over 60 years, compounds have been available that competitively antagonize many of the actions of histamine on smooth muscle. However, not until the H2-receptor antagonist burimamide was described in 1972 was it possible to antagonize the gastric acid-stimulating activity of histamine. The development of selective H2-receptor antagonists has led to more effective therapy for peptic disease (see Chapter 62). Selective H3 and H4 antagonists are not yet available for clinical use. However, potent and partially selective experimental H3-receptor antagonists, thioperamide and clobenpropit, have been developed.

image HISTAMINE RECEPTOR ANTAGONISTS

H1-RECEPTOR ANTAGONISTS

Compounds that competitively block histamine or act as inverse agonists at H1 receptors have been used in the treatment of allergic conditions for many years, and in the discussion that follows are referred to as antagonists. Many H1antagonists are currently marketed in the USA. A large number are available without prescription, both alone and in combination formulations such as “cold pills” and “sleep aids” (see Chapter 63).

BASIC PHARMACOLOGY OF H1-RECEPTOR ANTAGONISTS

Chemistry & Pharmacokinetics

The H1 antagonists are conveniently divided into first-generation and second-generation agents. These groups are distinguished by the relatively strong sedative effects of most of the first-generation drugs. The first-generation agents are also more likely to block autonomic receptors. Second-generation H1 blockers are less sedating, owing in part to reduced distribution into the central nervous system. All the H1antagonists are stable amines with the general structure illustrated in Figure 16–1. Doses of some of these drugs are given in Table 16–2.

image

FIGURE 16–1 General structure of H1-antagonist drugs and examples of the major subgroups. Subgroup names are based on the shaded moieties.

TABLE 16–2 Some H1 antihistaminic drugs in clinical use.

image

These agents are rapidly absorbed after oral administration, with peak blood concentrations occurring in 1–2 hours. They are widely distributed throughout the body, and the first-generation drugs enter the central nervous system readily. Some of them are extensively metabolized, primarily by microsomal systems in the liver. Several of the second-generation agents are metabolized by the CYP3A4 system and thus are subject to important interactions when other drugs (such as ketoconazole) inhibit this subtype of P450 enzymes. Most of the drugs have an effective duration of action of 4–6 hours following a single dose, but meclizine and several second-generation agents are longer-acting, with a duration of action of 12–24 hours. The newer agents are considerably less lipid-soluble than the first-generation drugs and are substrates of the P-glycoprotein transporter in the blood-brain barrier; as a result they enter the central nervous system with difficulty or not at all. Many H1 antagonists have active metabolites. The active metabolites of hydroxyzine, terfenadine, and loratadine are available as drugs (cetirizine, fexofenadine, and desloratadine, respectively).

Pharmacodynamics

Both neutral H1 antagonists and inverse H1 agonists reduce or block the actions of histamine by reversible competitive binding to the H1 receptor. Several have been clearly shown to be inverse agonists, and it is possible that all act by this mechanism. They have negligible potency at the H2 receptor and little at the H3 receptor. For example, histamine-induced contraction of bronchiolar or gastrointestinal smooth muscle can be completely blocked by these agents, but histamine-stimulated gastric acid secretion and the stimulation of the heart are unaffected.

The first-generation H1-receptor antagonists have many actions in addition to blockade of the actions of histamine. The large number of these actions probably results from the similarity of the general structure (Figure 16–1) to the structure of drugs that have effects at muscarinic cholinoceptor, a adrenoceptor, serotonin, and local anesthetic receptor sites. Some of these actions are of therapeutic value and some are undesirable.

1.Sedation—A common effect of first-generation H1 antagonists is sedation, but the intensity of this effect varies among chemical subgroups (Table 16–2) and among patients as well. The effect is sufficiently prominent with some agents to make them useful as “sleep aids” (see Chapter 63) and unsuitable for daytime use. The effect resembles that of some antimuscarinic drugs and is considered very different from the disinhibited sedation produced by sedative-hypnotic drugs. Compulsive use has not been reported. At ordinary dosages, children occasionally (and adults rarely) manifest excitation rather than sedation. At very high toxic dose levels, marked stimulation, agitation, and even seizures may precede coma. Second-generation H1 antagonists have little or no sedative or stimulant actions. These drugs (or their active metabolites) also have far fewer autonomic effects than the first-generation antihistamines.

2.Antinausea and antiemetic actions—Several first-generation H1 antagonists have significant activity in preventing motion sickness (Table 16–2). They are less effective against an episode of motion sickness already present. Certain H1 antagonists, notably doxylamine (in Bendectin), were used widely in the past in the treatment of nausea and vomiting of pregnancy (see below). Although Bendectin was withdrawn in 1983, a similar formulation, combining doxylamine and pyridoxine (Diclegis), was approved by the FDA in 2013.

3.Antiparkinsonism effects—Some of the H1 antagonists, especially diphenhydramine, have significant acute suppressant effects on the extrapyramidal symptoms associated with certain antipsychotic drugs. This drug is given parenterally for acute dystonic reactions to antipsychotics.

4.Antimuscarinic actions—Many first-generation agents, especially those of the ethanolamine and ethylenediamine subgroups, have significant atropine-like effects on peripheral muscarinic receptors. This action may be responsible for some of the (uncertain) benefits reported for nonallergic rhinorrhea but may also cause urinary retention and blurred vision.

5.Adrenoceptor-blocking actions—Alpha-receptor-blocking effects can be demonstrated for many H1 antagonists, especially those in the phenothiazine subgroup, eg, promethazine. This action may cause orthostatic hypotension in susceptible individuals. Beta-receptor blockade is not significant.

6.Serotonin-blocking actions—Strong blocking effects at serotonin receptors have been demonstrated for some first-generation H1 antagonists, notably cyproheptadine. This drug is promoted as an antiserotonin agent and is discussed with that drug group. Nevertheless, its structure resembles that of the phenothiazine antihistamines, and it is a potent H1-blocking agent.

7.Local anesthesia—Several first-generation H1 antagonists are potent local anesthetics. They block sodium channels in excitable membranes in the same fashion as procaine and lidocaine. Diphenhydramine and promethazine are actually more potent than procaine as local anesthetics. They are occasionally used to produce local anesthesia in patients allergic to conventional local anesthetic drugs. A small number of these agents also block potassium channels; this action is discussed below (see Toxicity).

8.Other actions—Certain H1 antagonists, eg, cetirizine, inhibit mast cell release of histamine and some other mediators of inflammation. This action is not due to H1-receptor blockade and may reflect an H4-receptor effect (see below). The mechanism is not fully understood but could play a role in the beneficial effects of these drugs in the treatment of allergies such as rhinitis. A few H1 antagonists (eg, terfenadine, acrivastine) have been shown to inhibit the P-glycoprotein transporter found in cancer cells, the epithelium of the gut, and the capillaries of the brain. The significance of this effect is not known.

CLINICAL PHARMACOLOGY OF H1-RECEPTOR ANTAGONISTS

Clinical Uses

First-generation H1-receptor blockers are still commonly used over-the-counter drugs. The prevalence of allergic conditions and the relative safety of the drugs contribute to this heavy use. However, the fact that they do cause sedation contributes to heavy prescribing as well as over-the-counter use of second-generation antihistamines.

A. Allergic Reactions

The H1 antihistaminic agents are often the first drugs used to prevent or treat the symptoms of allergic reactions. In allergic rhinitis (hay fever), the H1 antagonists are second-line drugs after glucocorticoids administered by nasal spray. In urticaria, in which histamine is the primary mediator, the H1 antagonists are the drugs of choice and are often quite effective if given before exposure. However, in bronchial asthma, which involves several mediators, the H1antagonists are largely ineffective.

Angioedema may be precipitated by histamine release but appears to be maintained by peptide kinins that are not affected by antihistaminic agents. For atopic dermatitis, antihistaminic drugs such as diphenhydramine are used mostly for their sedative side effect, which reduces awareness of itching.

The H1 antihistamines used for treating allergic conditions such as hay fever are usually selected with the goal of minimizing sedative effects; in the USA, the drugs in widest use are the alkylamines and the second-generation nonsedating agents. However, the sedative effect and the therapeutic efficacy of different agents vary widely among individuals. In addition, the clinical effectiveness of one group may diminish with continued use, and switching to another group may restore drug effectiveness for as yet unexplained reasons.

The second-generation H1 antagonists are used mainly for the treatment of allergic rhinitis and chronic urticaria. Several double-blind comparisons with older agents (eg, chlorpheniramine) indicated about equal therapeutic efficacy. However, sedation and interference with safe operation of machinery, which occur in about 50% of subjects taking first-generation antihistamines, occurred in only about 7% of subjects taking second-generation agents. The newer drugs are much more expensive, even in over-the-counter generic formulations.

B. Motion Sickness and Vestibular Disturbances

Scopolamine (see Chapter 8) and certain first-generation H1 antagonists are the most effective agents available for the prevention of motion sickness. The antihistaminic drugs with the greatest effectiveness in this application are diphenhydramine and promethazine. Dimenhydrinate, which is promoted almost exclusively for the treatment of motion sickness, is a salt of diphenhydramine and has similar efficacy. The piperazines (cyclizine and meclizine) also have significant activity in preventing motion sickness and are less sedating than diphenhydramine in most patients. Dosage is the same as that recommended for allergic disorders (Table 16–2). Both scopolamine and the H1antagonists are more effective in preventing motion sickness when combined with ephedrine or amphetamine.

It has been claimed that the antihistaminic agents effective in prophylaxis of motion sickness are also useful in Ménière’s syndrome, but efficacy in the latter condition is not established.

C. Nausea and Vomiting of Pregnancy

Several H1-antagonist drugs have been studied for possible use in treating “morning sickness.” The piperazine derivatives were withdrawn from such use when it was demonstrated that they have teratogenic effects in rodents. Doxylamine, an ethanolamine H1 antagonist, was promoted for this application as a component of Bendectin, a prescription medication that also contained pyridoxine. Possible teratogenic effects of doxylamine were widely publicized in the lay press after 1978 as a result of a few case reports of fetal malformation that occurred after maternal ingestion of Bendectin. However, several large prospective studies disclosed no increase in the incidence of birth defects, thereby justifying the reintroduction of a similar product.

Toxicity

The wide spectrum of nonantihistaminic effects of the H1 antihistamines is described above. Several of these effects (sedation, antimuscarinic action) have been used for therapeutic purposes, especially in over-the-counter remedies (see Chapter 63). Nevertheless, these two effects constitute the most common undesirable actions when these drugs are used to block histamine receptors.

Less common toxic effects of systemic use include excitation and convulsions in children, postural hypotension, and allergic responses. Drug allergy is relatively common after topical use of H1 antagonists. The effects of severe systemic overdosage of the older agents resemble those of atropine overdosage and are treated in the same way (see Chapters 8 and 58). Overdosage of astemizole or terfenadine may induce cardiac arrhythmias; the same effect may be caused at normal dosage by interaction with enzyme inhibitors (see Drug Interactions). These drugs are no longer marketed in the USA.

Drug Interactions

Lethal ventricular arrhythmias occurred in several patients taking either of the early second-generation agents, terfenadine or astemizole, in combination with ketoconazole, itraconazole, or macrolide antibiotics such as erythromycin. These antimicrobial drugs inhibit the metabolism of many drugs by CYP3A4 and cause significant increases in blood concentrations of the antihistamines. The mechanism of this toxicity involves blockade of the HERG (IKr) potassium channels in the heart that contribute to repolarization of the action potential (see Chapter 14). The result is prolongation and a change in shape of the action potential, and these changes lead to arrhythmias. Both terfenadine and astemizole were withdrawn from the US market in recognition of these problems. Where still available, terfenadine and astemizole should be considered to be contraindicated in patients taking ketoconazole, itraconazole, or macrolides and in patients with liver disease. Grapefruit juice also inhibits CYP3A4 and has been shown to increase blood levels of terfenadine significantly.

For those H1 antagonists that cause significant sedation, concurrent use of other drugs that cause central nervous system depression produces additive effects and is contraindicated while driving or operating machinery. Similarly, the autonomic blocking effects of older antihistamines are additive with those of antimuscarinic and α-blocking drugs.

H2-RECEPTOR ANTAGONISTS

The development of H2-receptor antagonists was based on the observation that H1 antagonists had no effect on histamine-induced acid secretion in the stomach. Molecular manipulation of the histamine molecule resulted in drugs that blocked acid secretion and had no H1 agonist or antagonist effects. Like the other histamine receptors, the H2 receptor displays constitutive activity, and some H2 blockers are inverse agonists.

The high prevalence of peptic ulcer disease created great interest in the therapeutic potential of the H2-receptor antagonists when first discovered. Although these agents are not the most efficacious available, their ability to reduce gastric acid secretion with very low toxicity has made them extremely popular as over-the-counter preparations. These drugs are discussed in more detail in Chapter 62.

H3- & H4-RECEPTOR ANTAGONISTS

Although no selective H3 or H4 ligands are presently available for general clinical use, there is great interest in their therapeutic potential. H3-selective ligands may be of value in sleep disorders, narcolepsy, obesity, and cognitive and psychiatric disorders. Tiprolisant, an inverse H3-receptor agonist, has been shown to reduce sleep cycles in mutant mice and in humans with narcolepsy. Increased obesity has been demonstrated in both H1- and H3-receptor knockout mice; however, H3 inverse agonists decrease feeding in obese mouse models. As noted in Chapter 29, several atypical antipsychotic drugs have significant affinity for H3 receptors (and cause weight gain).

Because of the homology between the H3 and H4 receptors, some H3 ligands also have affinity for the H4 receptor. H4 blockers have potential in chronic inflammatory conditions such as asthma, in which eosinophils and mast cells play a prominent role. No selective H4 ligand is available for use in humans, but in addition to research agents listed in Table 16–1, many H1-selective blockers (eg, diphenhydramine, cetirizine, loratadine) show some affinity for this receptor. Several studies have suggested that H4-receptor antagonists may be useful in pruritus, asthma, allergic rhinitis, and pain conditions.

image SEROTONIN (5-HYDROXYTRYPTAMINE)

Before the identification of 5-hydroxytryptamine (5-HT), it was known that when blood is allowed to clot, a vasoconstrictor (tonic) substance is released from the clot into the serum. This substance was called serotonin. Independent studies established the existence of a smooth muscle stimulant in intestinal mucosa. This was called enteramine. The synthesis of 5-hydroxytryptamine in 1951 led to the identification of serotonin and enteramine as the same metabolite of 5-hydroxytryptophan.

Serotonin is an important neurotransmitter, a local hormone in the gut, a component of the platelet clotting process, and is thought to play a role in migraine headache and several other clinical conditions, including carcinoid syndrome. This syndrome is an unusual manifestation of carcinoid tumor, a neoplasm of enterochromaffin cells. In patients whose tumor is not surgically resectable, a serotonin antagonist may constitute a useful treatment.

BASIC PHARMACOLOGY OF SEROTONIN

Chemistry & Pharmacokinetics

Like histamine, serotonin is widely distributed in nature, being found in plant and animal tissues, venoms, and stings. It is synthesized in biologic systems from the amino acid L-tryptophan by hydroxylation of the indole ring followed by decarboxylation of the amino acid (Figure 16–2). Hydroxylation at C5 by tryptophan hydroxylase-1 is the rate-limiting step and can be blocked by p-chlorophenylalanine (PCPA; fenclonine) and by p-chloroamphetamine. These agents have been used experimentally to reduce serotonin synthesis in carcinoid syndrome but are too toxic for general clinical use.

image

FIGURE 16–2 Synthesis of serotonin and melatonin from L-tryptophan.

After synthesis, the free amine is stored in vesicles or is rapidly inactivated, usually by oxidation by monoamine oxidase (MAO). In the pineal gland, serotonin serves as a precursor of melatonin, a melanocyte-stimulating hormone that has complex effects in several tissues. In mammals (including humans), over 90% of the serotonin in the body is found in enterochromaffin cells in the gastrointestinal tract. In the blood, serotonin is found in platelets, which are able to concentrate the amine by means of an active serotonin transporter mechanism (SERT) similar to that in the membrane of serotonergic nerve endings. Once transported into the platelet or nerve ending, 5-HT is concentrated in vesicles by a vesicle-associated transporter (VAT) that is blocked by reserpine. Serotonin is also found in the raphe nuclei of the brainstem, which contain cell bodies of serotonergic neurons that synthesize, store, and release serotonin as a transmitter. Stored serotonin can be depleted by reserpine in much the same manner as this drug depletes catecholamines from vesicles in adrenergic nerves and the adrenal medulla (see Chapter 6).

Brain serotonergic neurons are involved in numerous diffuse functions such as mood, sleep, appetite, and temperature regulation, as well as the perception of pain, the regulation of blood pressure, and vomiting (see Chapter 21). Serotonin is clearly involved in psychiatric depression (see Chapter 30) and also appears to be involved in conditions such as anxiety and migraine. Serotonergic neurons are found in the enteric nervous system of the gastrointestinal tract and around blood vessels. In rodents (but not in humans), serotonin is also found in mast cells.

The function of serotonin in enterochromaffin cells is not fully understood. These cells synthesize serotonin, store the amine in a complex with adenosine triphosphate (ATP) and other substances in granules, and release serotonin in response to mechanical and neuronal stimuli. This serotonin interacts in a paracrine fashion with several different 5-HT receptors in the gut (see Chapter 62). Some of the released serotonin diffuses into blood vessels and is taken up and stored in platelets.

Serotonin is metabolized by MAO, and the intermediate product, 5-hydroxyindoleacetaldehyde, is further oxidized by aldehyde dehydrogenase to 5-hydroxyindoleacetic acid (5-HIAA). In humans consuming a normal diet, the excretion of 5-HIAA is a measure of serotonin synthesis. Therefore, the 24-hour excretion of 5-HIAA can be used as a diagnostic test for tumors that synthesize excessive quantities of serotonin, especially carcinoid tumor. A few foods (eg, bananas) contain large amounts of serotonin or its precursors and must be prohibited during such diagnostic tests.

Pharmacodynamics

A. Mechanisms of Action

Serotonin exerts many actions and, like histamine, displays many species differences, making generalizations difficult. The actions of serotonin are mediated through a remarkably large number of cell membrane receptors. The serotonin receptors that have been characterized thus far are listed in Table 16–3. Seven families of 5-HT-receptor subtypes (those given numeric subscripts 1 through 7) have been identified, six involving G protein-coupled receptors of the usual 7-transmembrane serpentine type and one a ligand-gated ion channel. The latter (5-HT3) receptor is a member of the nicotinic family of Na+/K+ channel proteins.

TABLE 16–3 Serotonin receptor subtypes currently recognized. (See also Chapter 21.)

image

B. Tissue and Organ System Effects

1.Nervous system—Serotonin is present in a variety of sites in the brain. Its role as a neurotransmitter and its relation to the actions of drugs acting in the central nervous system are discussed in Chapters 21 and 30. Serotonin is also a precursor of melatonin in the pineal gland (Figure 16–2; see Box: Melatonin Pharmacology). Repinotan, a 5-HT1A agonist currently in clinical trials, appears to have some antinociceptive action at higher doses while reversing opioid-induced respiratory depression.

5-HT3 receptors in the gastrointestinal tract and in the vomiting center of the medulla participate in the vomiting reflex (see Chapter 62). They are particularly important in vomiting caused by chemical triggers such as cancer chemotherapy drugs. 5-HT1P and 5-HT4 receptors also play important roles in enteric nervous system function.

Melatonin Pharmacology

Melatonin is N-acetyl-5-methoxytryptamine (Figure 16–2), a simple methoxylated and N-acetylated product of serotonin found in the pineal gland. It is produced and released primarily at night and has long been suspected of playing a role in diurnal cycles of animals and the sleep-wake behavior of humans. Melatonin receptors have been characterized in the central nervous system and several peripheral tissues. In the brain, MT1 and MT2 receptors are found in membranes of neurons in the suprachiasmatic nucleus of the hypothalamus, an area associated—from lesioning experiments—with circadian rhythm. MT1and MT2 are seven-transmembrane Gi protein-coupled receptors. The result of receptor binding is inhibition of adenylyl cyclase. A third receptor, MT3, is an enzyme; binding to this site has a poorly defined physiologic role, possibly related to intraocular pressure. Activation of the MT1 receptor results in sleepiness, whereas the MT2 receptor may be related to the light-dark synchronization of the biologic circadian clock. Melatonin has also been implicated in energy metabolism and obesity, and administration of the agent reduces body weight in certain animal models. However, its role in these processes is poorly understood and there is no evidence that melatonin itself is of any value in obesity in humans. Other studies suggest that melatonin has antiapoptotic effects in experimental models. Recent research implicates melatonin receptors in depressive disorders.

Melatonin is promoted commercially as a sleep aid by the food supplement industry (see Chapter 64). There is an extensive literature supporting its use in ameliorating jet lag. It is used in oral doses of 0.5–5 mg, usually administered at the destination bedtime. Ramelteon is a selective MT1 and MT2 agonist that is approved for the medical treatment of insomnia. This drug has no addiction liability (it is not a controlled substance), and it appears to be distinctly more efficacious than melatonin (but less efficacious than benzodiazepines) as a hypnotic. It is metabolized by P450 enzymes and should not be used in individuals taking CYP1A2 inhibitors. It has a half-life of 1–3 hours and an active metabolite with a half-life of up to 5 hours. Ramelteon may increase prolactin levels. Tasimelteon is a newer MT1 and MT2agonist that is approved for non-24-hour sleep-wake disorder. Agomelatine,an MT1 and MT2 agonist and a 5-HT2C antagonist, is approved in Europe for use in major depressive disorder.

Like histamine, serotonin is a potent stimulant of pain and itch sensory nerve endings and is responsible for some of the symptoms caused by insect and plant stings. In addition, serotonin is a powerful activator of chemosensitive endings located in the coronary vascular bed. Activation of 5-HT3 receptors on these afferent vagal nerve endings is associated with the chemoreceptor reflex (also known as the Bezold-Jarisch reflex). The reflex response consists of marked bradycardia and hypotension, and its physiologic role is uncertain. The bradycardia is mediated by vagal outflow to the heart and can be blocked by atropine. The hypotension is a consequence of the decrease in cardiac output that results from bradycardia. A variety of other agents can activate the chemoreceptor reflex. These include nicotinic cholinoceptor agonists and some cardiac glycosides, eg, ouabain.

Although serotonergic neurons are not found below the site of injury to the adult spinal cord, constitutive activity of 5-HT receptors may play a role following such a lesion—administration of 5-HT2 blockers appears to reduce skeletal muscle spasm following this type of injury.

2.Respiratory system—Serotonin has a small direct stimulant effect on bronchiolar smooth muscle in normal humans, probably via 5-HT2A receptors. It also appears to facilitate acetylcholine release from bronchial vagal nerve endings. In patients with carcinoid syndrome, episodes of bronchoconstriction occur in response to elevated levels of the amine or peptides released from the tumor. Serotonin may also cause hyperventilation as a result of the chemoreceptor reflex or stimulation of bronchial sensory nerve endings.

3.Cardiovascular system—Serotonin directly causes the contraction of vascular smooth muscle, mainly through 5-HT2 receptors. In humans, serotonin is a powerful vasoconstrictor except in skeletal muscle and the heart, where it dilates blood vessels.

At least part of the 5-HT-induced vasodilation requires the presence of vascular endothelial cells. When the endothelium is damaged, coronary vessels are constricted by 5-HT. As noted previously, serotonin can also elicit reflex bradycardia by activation of 5-HT3 receptors on chemoreceptor nerve endings. A triphasic blood pressure response is often seen following injection of serotonin in experimental animals. Initially, there is a decrease in heart rate, cardiac output, and blood pressure caused by the chemoreceptor response. After this decrease, blood pressure increases as a result of vasoconstriction. The third phase is again a decrease in blood pressure attributed to vasodilation in vessels supplying skeletal muscle. In contrast, pulmonary and renal vessels seem very sensitive to the vasoconstrictor action of serotonin.

Studies in knockout mice suggest that 5-HT, acting on 5-HT1A, 5-HT2, and 5-HT4 receptors, is needed for normal cardiac development in the fetus. On the other hand, chronic exposure of adults to 5-HT2Bagonists is associated with valvulopathy and adult mice lacking the 5-HT2B receptor gene are protected from cardiac hypertrophy. Preliminary studies suggest that 5-HT2B antagonists can prevent development of pulmonary hypertension in animal models.

Serotonin also constricts veins, and venoconstriction with increased capillary filling appears to be responsible for the flush that is observed after serotonin administration or release from a carcinoid tumor. Serotonin has small direct positive chronotropic and inotropic effects on the heart, which are probably of no clinical significance. However, prolonged elevation of the blood level of serotonin (which occurs in carcinoid syndrome) is associated with pathologic alterations in the endocardium (subendocardial fibroplasia), which may result in valvular or electrical malfunction.

Serotonin Syndrome and Similar Syndromes

Excess synaptic serotonin causes a serious, potentially fatal syndrome that is diagnosed on the basis of a history of administration of a serotonergic drug within recent weeks and physical findings. It has some characteristics in common with neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH), but its pathophysiology and management are quite different (Table 16–4).

As suggested by the drugs that precipitate it, serotonin syndrome occurs when overdose with a single drug, or concurrent use of several drugs, results in excess serotonergic activity in the central nervous system. It is predictable and not idiosyncratic, but milder forms may easily be misdiagnosed. In experimental animal models, many of the signs of the syndrome can be reversed by administration of 5-HT2antagonists; however, other 5-HT receptors may be involved as well. Dantrolene is of no value, unlike the treatment of MH.

NMS is idiosyncratic rather than predictable and appears to be associated with hypersensitivity to the parkinsonism-inducing effects of D2-blocking antipsychotics in certain individuals. MH is associated with a genetic defect in the RyR1 calcium channel of skeletal muscle sarcoplasmic reticulum that permits uncontrolled calcium release from the sarcoplasmic reticulum when precipitating drugs are given (see Chapter 27).

Serotonin causes blood platelets to aggregate by activating 5-HT2 receptors. This response, in contrast to aggregation induced during normal clot formation, is not accompanied by the release of serotonin stored in the platelets. The physiologic role of this effect is unclear.

4.Gastrointestinal tract—Serotonin is a powerful stimulant of gastrointestinal smooth muscle, increasing tone and facilitating peristalsis. This action is caused by the direct action of serotonin on 5-HT2smooth muscle receptors plus a stimulating action on ganglion cells located in the enteric nervous system (see Chapter 6). 5-HT1A and 5-HT7 receptors may also be involved. Activation of 5-HT4 receptors in the enteric nervous system causes increased acetylcholine release and thereby mediates a motility-enhancing or “prokinetic” effect of selective serotonin agonists such as cisapride. These agents are useful in several gastrointestinal disorders (see Chapter 62). Overproduction of serotonin (and other substances) in carcinoid tumor is associated with severe diarrhea. Serotonin has little effect on gastrointestinal secretions, and what effects it has are generally inhibitory.

5.Skeletal muscle and the eye—5-HT2 receptors are present on skeletal muscle membranes, but their physiologic role is not understood. As discussed in the box, serotonin syndrome is associated with skeletal muscle contractions and precipitated when MAO inhibitors are given with serotonin agonists, especially antidepressants of the selective serotonin reuptake inhibitor class (SSRIs; see Chapter 30). Although the hyperthermia of serotonin syndrome results from excessive muscle contraction, serotonin syndrome is probably caused by a central nervous system effect of these drugs (Table 16–4 and Box: Serotonin Syndrome and Similar Syndromes).

TABLE 16–4 Characteristics of serotonin syndrome and other hyperthermic syndromes.

image

Studies in animal models of glaucoma indicate that 5-HT2A agonists reduce intraocular pressure. This action can be blocked by ketanserin and similar 5-HT2 antagonists.

CLINICAL PHARMACOLOGY OF SEROTONIN

Serotonin Agonists

Serotonin has no clinical applications as a drug. However, several receptor subtype-selective agonists have proved to be of value. Buspirone, a 5-HT1A agonist, has received attention as an effective nonbenzodiazepine anxiolytic (see Chapter 22). Appetite suppression appears to be associated with agonist action at 5-HT2C receptors in the central nervous system, and dexfenfluramine, a selective 5-HT agonist, was widely used as an appetite suppressant but was withdrawn because of cardiac valvulopathy. Lorcaserin, another 5-HT2C agonist, has recently been approved by the FDA for use as a weight-loss medication (see Box: Treatment Of Obesity).

Treatment of Obesity

It is said that much of the world is experiencing an “epidemic of obesity.” This statement is based on statistics showing that in the USA and many other developed countries, 30–40% of the population is above optimal weight, and that the excess weight (especially abdominal fat) is often associated with the metabolic syndrome and increased risks of cardiovascular disease and diabetes. Since eating behavior is an expression of endocrine, neurophysiologic, and psychological processes, prevention and treatment of obesity are challenging. There is considerable scientific and financial interest in developing pharmacologic therapy for the condition.

Although obesity can be defined as excess adipose tissue, it is currently quantitated by means of the body mass index (BMI), calculated from BMI = weight (in kilograms)/height2 (in meters). Using this measure, the range of normal BMI is defined as 18.5–24.9; overweight, 25–29.9; obese, 30–39.9; and morbidly obese (ie, at very high risk), ≥ 40. Some extremely muscular individuals may have a BMI higher than 25 and no excess fat; however, the BMI scale generally correlates with the degree of obesity and with risk. A second metric, which may be an even better predictor of cardiovascular risk, is the ratio of waist measurement to body height; risk is lower if this ratio is less than 0.5.

Although the cause of obesity can be simply stated as energy intake (dietary calories) that exceeds energy output (resting metabolism plus exercise), the actual physiology of weight control is extremely complex, and the pathophysiology of obesity is still poorly understood. Many hormones and neuronal mechanisms regulate intake (appetite, satiety), processing (absorption, conversion to fat, glycogen, etc), and output (thermogenesis, muscle work). The fact that a large number of hormones reduce appetite (eTable 16–4.1) might appear to offer many targets for weight-reducing drug therapy, but despite intensive research, no available pharmacologic therapy has succeeded in maintaining a weight loss of over 10% for 1 year. Furthermore, the social and psychological aspects of eating are powerful influences that are independent of or only partially dependent on the physiologic control mechanisms. In contrast, bariatric (weight-reducing) surgery readily achieves a sustained weight loss of 10–40%. Furthermore, surgery that bypasses the stomach and upper small intestine (but not simple restrictive banding) rapidly reverses some aspects of the metabolic syndrome even before significant loss of weight. However, even a 5–10% loss of weight is associated with a reduction in blood pressure and improved glycemic control. Gastrointestinal flora also influence metabolic efficiency and research in mice suggests that altering the flora can lead to weight gain or loss.

Until approximately 15 years ago, the most popular and successful appetite suppressants were the nonselective 5-HT2 agonists fenfluramine and dexfenfluramine. Combined with phentermine as Fen-Phenand Dex-Phen,they were moderately effective. However, these 5-HT2 agonists were found to cause pulmonary hypertension and cardiac valve defects and were withdrawn.

Older drugs still available in the USA and some other countries include phenylpropanolamine, benzphetamine, amphetamine, methamphetamine, phentermine, diethylpropion, mazindol, and phendimetrazine. These drugs are all amphetamine mimics and are central nervous system appetite suppressants; they are generally helpful only during the first few weeks of therapy. Their toxicity is significant and includes hypertension (with a risk of cerebral hemorrhage) and addiction liability.

Orlistat and lorcaserin are the only single-agent non-amphetamine drugs currently approved in the USA for the treatment of obesity. In addition, an agent that combines phentermine and topiramate(Qsymia) has recently been approved. These drugs have been intensely studied and their properties are listed in Table 16–5. Clinical trials and phase 4 reports suggest that all three agents are modestly effective for the duration of therapy (up to 1 year) and are probably safer than the single agent amphetamine mimics. However, they do not produce more than a 5–10% loss of weight. A combination of naltrexone and bupropion (Contrave) has just been approved and seems to be similarly effective. Sibutramine and rimonabant were marketed for several years but were withdrawn because of increasing evidence of cardiovascular toxicity.

Because of the low efficacy and the toxicity of the available drugs, intensive research continues. (Some drugs approved for other indications that reduce appetite and possible future weight-loss drugs are set forth in eTable 16–5.1) Because of the redundancy of the physiologic mechanisms for control of body weight, it seems likely that polypharmacy targeting multiple pathways will be needed to achieve success.

1See online version.

TABLE 16–5 Newer antiobesity drugs and their effects.

image

5-HT1D/1B Agonists & Migraine Headache

The 5-HT1D/1B agonists (triptans, eg, sumatriptan) are used almost exclusively for migraine headache. Migraine in its “classic” form is characterized by an aura of variable duration that may involve nausea, vomiting, visual scotomas or even hemianopsia, and speech abnormalities; the aura is followed by a severe throbbing unilateral headache that lasts for a few hours to 1–2 days. “Common” migraine lacks the aura phase, but the headache is similar. After a century of intense study, the pathophysiology of migraine is still poorly understood. Although the symptom pattern and duration of prodrome and headache vary markedly among patients, the severity of migraine headache justifies vigorous therapy in the great majority of cases.

Migraine involves the trigeminal nerve distribution to intracranial (and possibly extracranial) arteries. These nerves release peptide neurotransmitters, especially calcitonin gene-related peptide (CGRP; see Chapter 17), an extremely powerful vasodilator. Substance P and neurokinin A may also be involved. Extravasation of plasma and plasma proteins into the perivascular space appears to be a common feature of animal migraine models and is found in biopsy specimens from migraine patients. This effect probably reflects the action of the neuropeptides on the vessels. The mechanical stretching caused by this perivascular edema may be the immediate cause of activation of pain nerve endings in the dura. The onset of headache is sometimes associated with a marked increase in amplitude of temporal artery pulsations, and relief of pain by administration of effective therapy is sometimes accompanied by diminution of these pulsations.

The mechanisms of action of drugs used in migraine are poorly understood, in part because they include such a wide variety of drug groups and actions. In addition to the triptans, these include ergot alkaloids, nonsteroidal anti-inflammatory analgesic agents, β-adrenoceptor blockers, calcium channel blockers, tricyclic antidepressants and SSRIs, and several antiseizure agents. Furthermore, some of these drug groups are effective only for prophylaxis and not for the acute attack.

Two primary hypotheses have been proposed to explain the actions of these drugs. First, the triptans, the ergot alkaloids, and antidepressants may activate 5-HT1D/1B receptors on presynaptic trigeminal nerve endings to inhibit the release of vasodilating peptides, and antiseizure agents may suppress excessive firing of these nerve endings. Second, the vasoconstrictor actions of direct 5-HT agonists (the triptans and ergot) may prevent vasodilation and stretching of the pain endings. It is possible that both mechanisms contribute in the case of some drugs.

Sumatriptan and its congeners are currently first-line therapy for acute severe migraine attacks in most patients (Figure 16–3). However, they should not be used in patients at risk for coronary artery disease. Anti-inflammatory analgesics such as aspirin and ibuprofen are often helpful in controlling the pain of migraine. Rarely, parenteral opioids may be needed in refractory cases. For patients with very severe nausea and vomiting, parenteral metoclopramide may be helpful.

image

FIGURE 16–3 Effects of sumatriptan (734 patients) or placebo (370 patients) on symptoms of acute migraine headache 60 minutes after injection of 6 mg subcutaneously. All differences between placebo and sumatriptan were statistically significant. (Data from Cady RK et al: Treatment of acute migraine with subcutaneous sumatriptan. JAMA 1991;265:2831.)

Sumatriptan and the other triptans are selective agonists for 5-HT1D and 5-HT1B receptors; the similarity of the triptan structure to that of the 5-HT nucleus can be seen in the structure below. These receptor types are found in cerebral and meningeal vessels and mediate vasoconstriction. They are also found on neurons and probably function as presynaptic inhibitory receptors.

image

The efficacies of all the triptan 5-HT1 agonists in migraine are equal to each other and equivalent to or greater than those of other acute drug treatments, eg, parenteral, oral, and rectal ergot alkaloids. The pharmacokinetics of the triptans differ significantly and are set forth in Table 16–6. Most adverse effects are mild and include altered sensations (tingling, warmth, etc), dizziness, muscle weakness, neck pain, and for parenteral sumatriptan, injection site reactions. Chest discomfort occurs in 1–5% of patients, and chest pain has been reported, probably because of the ability of these drugs to cause coronary vasospasm. They are therefore contraindicated in patients with coronary artery disease and in patients with angina. Another disadvantage is the fact that their duration of effect (especially that of almotriptan, sumatriptan, rizatriptan, and zolmitriptan, Table 16–6) is often shorter than the duration of the headache. As a result, several doses may be required during a prolonged migraine attack, but their adverse effects limit the maximum safe daily dosage. Naratriptan and eletriptan are contraindicated in patients with severe hepatic or renal impairment or peripheral vascular syndromes; frovatriptan in patients with peripheral vascular disease; and zolmitriptan in patients with Wolff-Parkinson-White syndrome. The brand name triptans are extremely expensive; thus generic sumatriptan should be used whenever possible.

TABLE 16–6 Pharmacokinetics of triptans.

image

Propranolol, amitriptyline, and some calcium channel blockers have been found to be effective for the prophylaxis of migraine in some patients. They are of no value in the treatment of acute migraine. The anticonvulsants valproic acid and topiramate (see Chapter 24) have also been found to have some prophylactic efficacy in migraine. Flunarizine, a calcium channel blocker used in Europe, has been reported in clinical trials to effectively reduce the severity of the acute attack and to prevent recurrences. Verapamil appears to have modest efficacy as prophylaxis against migraine.

Other Serotonin Agonists in Clinical Use

Cisapride, a 5-HT4 agonist, was used in the treatment of gastro-esophageal reflux and motility disorders. Because of toxicity, it is now available only for compassionate use in the USA. Tegaserod, a 5-HT4partial agonist, is used for irritable bowel syndrome with constipation. These drugs are discussed in Chapter 62.

Compounds such as fluoxetine and other SSRIs, which modulate serotonergic transmission by blocking reuptake of the transmitter, are among the most widely prescribed drugs for the management of depression and similar disorders. These drugs are discussed in Chapter 30.

SEROTONIN ANTAGONISTS

The actions of serotonin, like those of histamine, can be antagonized in several ways. Such antagonism is clearly desirable in those rare patients who have carcinoid tumor and may also be valuable in certain other conditions.

As noted, serotonin synthesis can be inhibited by p-chlorophenylalanine and p-chloroamphetamine. However, these agents are too toxic for general use. Storage of serotonin can be inhibited by the use of reserpine, but the sympatholytic effects of this drug (see Chapter 11) and the high levels of circulating serotonin that result from release prevent its use in carcinoid. Therefore, receptor blockade is the major therapeutic approach to conditions of serotonin excess.

SEROTONIN-RECEPTOR ANTAGONISTS

A wide variety of drugs with actions at other receptors (eg, a adrenoceptors, H1-histamine receptors) also have serotonin receptor-blocking effects. Phenoxybenzamine (see Chapter 10) has a long-lasting blocking action at 5-HT2receptors. In addition, the ergot alkaloids discussed in the last portion of this chapter are partial agonists at serotonin receptors.

Cyproheptadine resembles the phenothiazine antihistaminic agents in chemical structure and has potent H1-receptor-blocking as well as 5-HT2-blocking actions. The actions of cyproheptadine are predictable from its H1histamine and 5-HT receptor affinities. It prevents the smooth muscle effects of both amines but has no effect on the gastric secretion stimulated by histamine. It also has significant antimuscarinic effects and causes sedation.

The major clinical applications of cyproheptadine are in the treatment of the smooth muscle manifestations of carcinoid tumor and in cold-induced urticaria. The usual dosage in adults is 12–16 mg/d in three or four divided doses. It is of some value in serotonin syndrome, but because it is available only in tablet form, cyproheptadine must be crushed and administered by stomach tube in unconscious patients. The drug also appears to reduce muscle spasms following spinal cord injury, in which constitutive activity of 5-HT2C receptors is associated with increases in Ca2+ currents leading to spasms. Anecdotal evidence suggests some efficacy as an appetite stimulant in cancer, but controlled trials have yielded mixed results.

Ketanserin blocks 5-HT2 receptors on smooth muscle and other tissues and has little or no reported antagonist activity at other 5-HT or H1 receptors. However, this drug potently blocks vascular a1adrenoceptors. The drug blocks 5-HT2 receptors on platelets and antagonizes platelet aggregation promoted by serotonin. The mechanism involved in ketanserin’s hypotensive action probably involves α1adrenoceptor blockade more than 5-HT2 receptor blockade. Ketanserin is available in Europe for the treatment of hypertension and vasospastic conditions but has not been approved in the USA. Ritanserin,another 5-HT2 antagonist, has little or no α-blocking action. It has been reported to alter bleeding time and to reduce thromboxane formation, presumably by altering platelet function.

Ergot Poisoning: Not Just an Ancient Disease

As noted in the text, epidemics of ergotism, or poisoning by ergot-contaminated grain, are known to have occurred sporadically in ancient times and through the Middle Ages. It is easy to imagine the social chaos that might result if fiery pain, gangrene, hallucinations, convulsions, and abortions occurred simultaneously throughout a community in which all or most of the people believed in witchcraft, demonic possession, and the visitation of supernatural punishments upon humans for their misdeeds. Fortunately, such beliefs are uncommon today. However, ergotism has not disappeared. A most convincing demonstration of ergotism occurred in the small French village of Pont-Saint-Esprit in 1951. It was described in the British Medical Journal in 1951 (Gabbai et al, 1951) and in a later book-length narrative account (Fuller, 1968). Several hundred individuals suffered symptoms of hallucinations, convulsions, and ischemia—and several died—after eating bread made from contaminated flour. Similar events have occurred even more recently when poverty, famine, or incompetence resulted in the consumption of contaminated grain. Ergot toxicity caused by excessive self-medication with pharmaceutical ergot preparations is still occasionally reported.

Ondansetron is the prototypical 5-HT3 antagonist. This drug and its analogs are very important in the prevention of nausea and vomiting associated with surgery and cancer chemotherapy. They are discussed in Chapter 62.

Considering the diverse effects attributed to serotonin and the heterogeneous nature of 5-HT receptors, other selective 5-HT antagonists may prove to be clinically useful.

image THE ERGOT ALKALOIDS

Ergot alkaloids are produced by Claviceps purpurea, a fungus that infects grasses and grains—especially rye—under damp growing or storage conditions. This fungus synthesizes histamine, acetylcholine, tyramine, and other biologically active products in addition to a score or more of unique ergot alkaloids. These alkaloids affect a adrenoceptors, dopamine receptors, 5-HT receptors, and perhaps other receptor types. Similar alkaloids are produced by fungi parasitic to a number of other grass-like plants.

The accidental ingestion of ergot alkaloids in contaminated grain can be traced back more than 2000 years from descriptions of epidemics of ergot poisoning (ergotism). The most dramatic effects of poisoning are dementia with florid hallucinations; prolonged vasospasm, which may result in gangrene; and stimulation of uterine smooth muscle, which in pregnancy may result in abortion. In medieval times, ergot poisoning was called St. Anthony’s fire after the saint whose help was sought in relieving the burning pain of vasospastic ischemia. Identifiable epidemics have occurred sporadically up to modern times (see Box: Ergot Poisoning: Not Just an Ancient Disease) and mandate continuous surveillance of all grains used for food. Poisoning of grazing animals is common in many areas because the fungus may grow on pasture grasses.

In addition to the effects noted above, the ergot alkaloids produce a variety of other central nervous system and peripheral effects. Detailed structure-activity analysis and appropriate semisynthetic modifications have yielded a large number of agents of experimental and clinical interest.

BASIC PHARMACOLOGY OF ERGOT ALKALOIDS

Chemistry & Pharmacokinetics

Two major families of compounds that incorporate the tetracyclic ergoline nucleus may be identified; the amine alkaloids and the peptide alkaloids (Table 16–7). Drugs of therapeutic and toxicologic importance are found in both groups.

TABLE 16–7 Major ergoline derivatives (ergot alkaloids).

image

The ergot alkaloids are variably absorbed from the gastrointestinal tract. The oral dose of ergotamine is about 10 times larger than the intramuscular dose, but the speed of absorption and peak blood levels after oral administration can be improved by administration with caffeine (see below). The amine alkaloids are also absorbed from the rectum and the buccal cavity and after administration by aerosol inhaler. Absorption after intramuscular injection is slow but usually reliable. Semisynthetic analogs such as bromocriptine and cabergoline are well absorbed from the gastrointestinal tract.

The ergot alkaloids are extensively metabolized in the body. The primary metabolites are hydroxylated in the A ring, and peptide alkaloids are also modified in the peptide moiety.

Pharmacodynamics

A. Mechanism of Action

The ergot alkaloids act on several types of receptors. As shown by the color outlines in Table 16–7, the nuclei of both catecholamines (phenylethylamine, left panel) and 5-HT (indolethylamine, right panel) can be discerned in the ergoline nucleus. Their effects include agonist, partial agonist, and antagonist actions at a adrenoceptors and serotonin receptors (especially 5-HT1A and 5-HT1D; less for 5-HT2 and 5-HT3); and agonist or partial agonist actions at central nervous system dopamine receptors (Table 16–8). Furthermore, some members of the ergot family have a high affinity for presynaptic receptors, whereas others are more selective for postjunctional receptors. There is a powerful stimulant effect on the uterus that seems to be most closely associated with agonist or partial agonist effects at 5-HT2 receptors. Structural variations increase the selectivity of certain members of the family for specific receptor types.

TABLE 16–8 Effects of ergot alkaloids at several receptors.1

image

B. Organ System Effects

1.Central nervous system—As indicated by traditional descriptions of ergotism, certain of the naturally occurring alkaloids are powerful hallucinogens. Lysergic acid diethylamide (LSD; “acid”) is a synthetic ergot compound that clearly demonstrates this action. The drug has been used in the laboratory as a potent peripheral 5-HT2 antagonist, but good evidence suggests that its behavioral effects are mediated by agonist effects at prejunctional or postjunctional 5-HT2 receptors in the central nervous system. In spite of extensive research, no clinical value has been discovered for LSD’s dramatic central nervous system effects. Abuse of this drug has waxed and waned but is still widespread. It is discussed in Chapter 32.

Dopamine receptors in the central nervous system play important roles in extrapyramidal motor control and the regulation of pituitary prolactin release. The actions of the peptide ergoline bromocriptine on the extrapyramidal system are discussed in Chapter 28. Of all the currently available ergot derivatives, bromocriptine, cabergoline, and pergolide have the highest selectivity for the pituitary dopamine receptors. These drugs directly suppress prolactin secretion from pituitary cells by activating regulatory dopamine receptors (see Chapter 37). They compete for binding to these sites with dopamine itself and with other dopamine agonists such as apomorphine. They bind with high affinity and dissociate slowly.

2.Vascular smooth muscle—The actions of ergot alkaloids on vascular smooth muscle are drug-, species-, and vessel-dependent, so few generalizations are possible. In humans, ergotamine and similar compounds constrict most vessels in nanomolar concentrations (Figure 16–4). The vasospasm is prolonged. This response is partially blocked by conventional α-blocking agents. However, ergotamine’s effect is also associated with “epinephrine reversal” (see Chapter 10) and with blockade of the response to other a agonists. This dual effect reflects the drug’s partial agonist action (Table 16–7). Because ergotamine dissociates very slowly from the α receptor, it produces very long-lasting agonist and antagonist effects at this receptor. There is little or no effect at β adrenoceptors.

image

FIGURE 16–4 Effects of ergot derivatives on contraction of isolated segments of human basilar artery strips removed at surgery. All of the ergot derivatives are partial agonists; and all are more potent than the full agonists, norepinephrine and serotonin. DHE, dihydroergotamine; ERG, ergotamine; 5-HT, serotonin; MS, methysergide; MT, methylergometrine; NE, norepinephrine. (Reproduced, with permission, from Müller-Schweinitzer E. In: 5-Hydroxytryptamine Mechanisms in Primary Headaches. Olesen J, Saxena PR [editors]. Raven Press, 1992.)

Although much of the vasoconstriction elicited by ergot alkaloids can be ascribed to partial agonist effects at a adrenoceptors, some may be the result of effects at 5-HT receptors. Ergotamine, ergonovine, and methysergide all have partial agonist effects at 5-HT2 vascular receptors. The remarkably specific antimigraine action of the ergot derivatives was originally thought to be related to their actions on vascular serotonin receptors. Current hypotheses, however, emphasize their action on prejunctional neuronal 5-HT receptors.

After overdosage with ergotamine and similar agents, vasospasm is severe and prolonged (see Toxicity, below). This vasospasm is not easily reversed by a antagonists, serotonin antagonists, or combinations of both.

Ergotamine is typical of the ergot alkaloids that have a strong vasoconstrictor spectrum of action. The hydrogenation of ergot alkaloids at the 9 and 10 positions (Table 16–6) yields dihydro derivatives that have reduced serotonin partial agonist and vasoconstrictor effects and increased selective α-receptor-blocking actions.

3.Uterine smooth muscle—The stimulant action of ergot alkaloids on the uterus, as on vascular smooth muscle, appears to combine a agonist, serotonin agonist, and other effects. Furthermore, the sensitivity of the uterus to the stimulant effects of ergot increases dramatically during pregnancy, perhaps because of increasing dominance of α1 receptors as pregnancy progresses. As a result, the uterus at term is more sensitive to ergot than earlier in pregnancy and far more sensitive than the nonpregnant organ.

In very small doses, ergot preparations can evoke rhythmic contraction and relaxation of the uterus. At higher concentrations, these drugs induce powerful and prolonged contracture. Ergonovine is more selective than other ergot alkaloids in affecting the uterus and is an agent of choice in obstetric applications of the ergot drugs although oxytocin, the peptide hormone, is preferred in most cases.

4.Other smooth muscle organs—In most patients, the ergot alkaloids have little or no significant effect on bronchiolar or urinary smooth muscle. The gastrointestinal tract, on the other hand, is quite sensitive. Nausea, vomiting, and diarrhea may be induced even by low doses in some patients. The effect is consistent with action on the central nervous system emetic center and on gastrointestinal serotonin receptors.

CLINICAL PHARMACOLOGY OF ERGOT ALKALOIDS

Clinical Uses

In spite of their significant toxicities, ergot alkaloids are still widely used in patients with migraine headache or pituitary dysfunction. They are used only occasionally in the postpartum patient.

A. Migraine

Ergot derivatives are highly specific for migraine pain; they are not analgesic for any other condition. Although the triptan drugs discussed above are preferred by most clinicians and patients, traditional therapy with ergotamine can also be effective when given during the prodrome of an attack; it becomes progressively less effective if delayed. Ergotamine tartrate is available for oral, sublingual, rectal suppository, and inhaler use. It is often combined with caffeine (100 mg caffeine for each 1 mg ergotamine tartrate) to facilitate absorption of the ergot alkaloid.

The vasoconstriction induced by ergotamine is long-lasting and cumulative when the drug is taken repeatedly, as in a severe migraine attack. Therefore, patients must be carefully informed that no more than 6 mg of the oral preparation may be taken for each attack and no more than 10 mg per week. For very severe attacks, ergotamine tartrate, 0.25–0.5 mg, may be given intravenously or intramuscularly. Dihydroergotamine, 0.5–1 mg intravenously, is favored by some clinicians for treatment of intractable migraine. Intranasal dihydroergotamine may also be effective. Methysergide, which was used for migraine prophylaxis in the past, was withdrawn because of toxicity, see below.

B. Hyperprolactinemia

Increased serum levels of the anterior pituitary hormone prolactin are associated with secreting tumors of the gland and also with the use of centrally acting dopamine antagonists, especially the D2-blocking antipsychotic drugs. Because of negative feedback effects, hyperprolactinemia is associated with amenorrhea and infertility in women as well as galactorrhea in both sexes. Rarely, the prolactin surge that occurs around the end-of-term pregnancy may be associated with heart failure; cabergoline has been used to treat this cardiac condition successfully.

Bromocriptine is extremely effective in reducing the high levels of prolactin that result from pituitary tumors and has even been associated with regression of the tumor in some cases. The usual dosage of bromocriptine is 2.5 mg two or three times daily. Cabergoline is similar but more potent. Bromocriptine has also been used in the same dosage to suppress physiologic lactation. However, serious postpartum cardiovascular toxicity has been reported in association with the latter use of bromocriptine or pergolide, and this application is discouraged (see Chapter 37).

C. Postpartum Hemorrhage

The uterus at term is extremely sensitive to the stimulant action of ergot, and even moderate doses produce a prolonged and powerful spasm of the muscle quite unlike natural labor. Therefore, ergot derivatives should be used only for control of postpartum uterine bleeding and should never be given before delivery. Oxytocin is the preferred agent for control of postpartum hemorrhage, but if this peptide agent is ineffective, ergonovine maleate, 0.2 mg given intramuscularly, can be tried. It is usually effective within 1–5 minutes and is less toxic than other ergot derivatives for this application. It is given at the time of delivery of the placenta or immediately afterward if bleeding is significant.

D. Diagnosis of Variant Angina

Ergonovine given intravenously produces prompt vasoconstriction during coronary angiography to diagnose variant angina if reactive segments of the coronary arteries are present. In Europe, methylergometrine has been used for this purpose.

E. Senile Cerebral Insufficiency

Dihydroergotoxine, a mixture of dihydro-a-ergocryptine and three similar dihydrogenated peptide ergot alkaloids (ergoloid mesylates), has been promoted for many years for the relief of senility and more recently for the treatment of Alzheimer’s dementia. There is no useful evidence that this drug has significant benefit.

Toxicity & Contraindications

The most common toxic effects of the ergot derivatives are gastrointestinal disturbances, including diarrhea, nausea, and vomiting. Activation of the medullary vomiting center and of the gastrointestinal serotonin receptors is involved. Since migraine attacks are often associated with these symptoms before therapy is begun, these adverse effects are rarely contraindications to the use of ergot.

A more dangerous toxic effect—usually associated with overdosage—of agents like ergotamine and ergonovine is prolonged vasospasm. This sign of vascular smooth muscle stimulation may result in gangrene and may require amputation. Bowel infarction has also been reported and may require resection. Vasospasm caused by ergot is refractory to most vasodilators, but infusion of large doses of nitroprusside or nitroglycerin has been successful in some cases.

Chronic therapy with methysergide was associated with connective tissue proliferation in the retroperitoneal space, the pleural cavity, and the endocardial tissue of the heart. These changes occurred insidiously over months and presented as hydronephrosis (from obstruction of the ureters) or a cardiac murmur (from distortion of the valves of the heart). In some cases, valve damage required surgical replacement. As a result, this drug was withdrawn from the US market. Similar fibrotic change has resulted from the chronic use of 5-HT agonists promoted in the past for weight loss (fenfluramine, dexfenfluramine).

Other toxic effects of the ergot alkaloids include drowsiness and, in the case of methysergide, occasional instances of central stimulation and hallucinations. In fact, methysergide was sometimes used as a substitute for LSD by members of the so-called drug culture.

Contraindications to the use of ergot derivatives consist of the obstructive vascular diseases, especially symptomatic coronary artery disease, and collagen diseases.

There is no evidence that ordinary use of ergotamine for migraine is hazardous in pregnancy. However, most clinicians counsel restraint in the use of the ergot derivatives by pregnant patients. Use to deliberately cause abortion is contraindicated because the high doses required often cause dangerous vasoconstriction.

SUMMARY Drugs with Actions on Histamine and Serotonin Receptors; Ergot Alkaloids

image

image

PREPARATIONS AVAILABLE

image

image

REFERENCES

Histamine

Arrang J-M, Morisset S, Gbahou F: Constitutive activity of the histamine H3 receptor. Trends Pharmacol Sci 2007;28:350.

Barnes PJ: Histamine and serotonin. Pulm Pharmacol Ther 2001;14:329.

Bond RA, Ijerman AP: Recent developments in constitutive receptor activity and inverse agonism, and their potential for GPCR drug discovery. Trend Pharmacol Sci 2006;27:92.

deShazo RD, Kemp SF: Pharmacotherapy of allergic rhinitis. www.UpToDate.com, 2013.

Jørgensen EA et al: Histamine and the regulation of body weight. Neuroendocrinology 2007;86:210.

Keet C: Recognition and management of food induced anaphylaxis. Pediatr Clin North Am 2011;58:377.

Niebyl JR: Nausea and vomiting in pregnancy. N Engl J Med 2010;363:1544.

Preuss H et al: Constitutive activity and ligand selectivity of human, guinea pig, rat, and canine histamine H2 receptors. J Pharmacol Exp Therap 2007;321:983.

Schaefer P: Urticaria: Evaluation and treatment. Am Fam Physician 2011;83:1078.

Smits RA, Leurs R, deEdech JP: Major advances in the development of histamine H4 receptor ligands. Drug Discov Today 2009;14:745.

Thurmond RL, Gelfand EW, Dunford PJ: The role of histamine H1 and H4 receptors in allergic inflammation: The search for new antihistamines. Nat Rev Drug Dis 2008;7:41.

Serotonin

Asghar MS et al: Evidence for a vascular factor in migraine. Ann Neurol 2011;69:635.

Bajwa ZH, Sabahat A: Acute treatment of migraine in adults. www.UpToDate.com, 2013.

Barrenetxe J, Delagrange P, Martinez JA: Physiologic and metabolic functions of melatonin. J Physiol Biochem 2004;60:61.

Boyer EW, Shannon M: The serotonin syndrome. N Engl J Med 2005;352:1112.

Wang Chong et al: Structural basis for molecular recognition at serotonin receptors. Science 2013;340:610.

D’Amico JM et al: Constitutively active 5-HT2/α1 receptors facilitate muscle spasms after human spinal cord injury. J Neurophysiol 2013;109:1473.

Elangbam CS: Drug-induced valvulopathy: An update. Toxicol Path 2010;38:837.

Frank C: Recognition and treatment of serotonin syndrome. Can Fam Physician 2008;54:988.

Loder E: Triptan therapy in migraine. N Engl J Med 2010;363:63.

Porvasnik SL et al: PRX-08066, a novel 5-hydroxytryptamine receptor 2B antagonist, reduces monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy in rats. J Pharmacol Exp Therap 2010;334:364.

Raymond JR et al: Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol Ther 2001;92:179.

Sack RL: Jet lag. N Engl J Med 2010;362:440.

Thompson AJ: Recent developments in 5-HT3 receptor pharmacology. Trends Pharmacol Sci 2013;34:100.

Ergot Alkaloids: Historical

Fuller JG: The Day of St. Anthony’s Fire. Macmillan, 1968; Signet, 1969.

Gabbai Dr, Lisbonne Dr, Pourquier Dr: Ergot poisoning at Pont St. Esprit. Br Med J 1951;Sept 15:650.

Ergot Alkaloids: Pharmacology

Dahlöf C, Van Den Brink A: Dihydroergotamine, ergotamine, methysergide and sumatriptan—Basic science in relation to migraine treatment. Headache 2012;52:707.

Dierckx RA et al: Intraarterial sodium nitroprusside infusion in the treatment of severe ergotism. Clin Neuropharmacol 1986;9:542.

Dildy GA: Postpartum hemorrhage: New management options. Clin Obstet Gynecol 2002;45:330.

Mantegani S, Brambilla E, Varasi M: Ergoline derivatives: Receptor affinity and selectivity. Farmaco 1999;54:288.

Porter JK, Thompson FN Jr: Effects of fescue toxicosis on reproduction in livestock. J Animal Sci 1992;70:1594.

Obesity

Adan RAH et al: Anti-obesity drugs and neural circuits of feeding. Trends Pharmacol Sci 2008;29:208.

Bloom SR et al: The obesity epidemic. Pharmacological challenges. Mol Interventions 2008;8:82.

Bray Ga: Drug therapy of obesity. www.uptodate.com, 2013.

CASE STUDY ANSWER

These patients demonstrate typical symptoms and signs caused by histamine. Fortunately, neither patient in this episode of food poisoning had significant laryngeal edema or bronchospasm. Certain types of fish, if improperly preserved, contain large quantities of histamine, due to the conversion—by bacteria contaminating the muscle tissue—of histadine to histamine. If consumed in sufficient amount, enough histamine can be absorbed to cause the clinical picture described. This syndrome is termed scombroid poisoning. Treatment with maximal doses of histamine blockers, especially H1 blockers, is usually sufficient to control the symptoms. Because this is not an allergic reaction, administration of epinephrine is not necessary unless hypotension or airway obstruction is severe. (See Edlow JA: The Deadly Dinner Party: And Other Medical Detective Stories. Yale University Press, 2009.)