Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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 IgGor IgM-mediated immune reactions that activate the complement cascade also release histamine from mast cells and basophils.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 Tand 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


Pharmacology_Katzung

Pharmacology_Katzung. 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 explosive 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. A. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 firstand 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).


Pharmacology_Katzung

Pharmacology_Katzung. 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. H4 receptors are found mainly on leukocytes in the bone marrow and circulating blood. H4 receptors appear to


Pharmacology_Katzung

Pharmacology_Katzung. mediated by a decrease in calcium influx through N-type calcium channels in nerve endings. H4 receptors are found mainly on leukocytes in the bone marrow and circulating blood. H4 receptors appear to have very important


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 16–1 Histamine receptor subtypes. CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 279 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 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 1Inverse agonist. cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol trisphosphate. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 2. 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. 3. 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. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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. 5. 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 under way to determine whether H3 agonists are useful in the treatment of obesity. 6.


Pharmacology_Katzung

Pharmacology_Katzung. 6. 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. 7.


Pharmacology_Katzung

Pharmacology_Katzung. 7. 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. 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. In pulmonary function laboratories, histamine aerosol has rarely been used as a provocative test of bronchial hyperreactivity. Histamine has no other current clinical applications.


Pharmacology_Katzung

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


Pharmacology_Katzung

Pharmacology_Katzung. 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. 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.


Pharmacology_Katzung

Pharmacology_Katzung. Histamine receptor antagonists represent a third approach to the reduction of histamine-mediated responses. For over 70 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 H1 antagonists 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). 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 H1 antagonists are stable amines with the general structure illustrated in Figure 16–1. Doses of some of these drugs are given in Table 16–2.


Pharmacology_Katzung

Pharmacology_Katzung. 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 H1 blockers 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


Pharmacology_Katzung

Pharmacology_Katzung. 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).


Pharmacology_Katzung

Pharmacology_Katzung. 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 X is: C or N Y is: C, O, or omitted X Y C C N CH OCH2 Diphenhydramine or dimenhydrinate NCH2 CH3 CH3 Alkylamine derivative Chlorpheniramine CH2 CH2CH Piperidine derivative N N CH3 CH3 Fexofenadine C OH N OH CH3 CH2 CH2 CH2 CH C FIGURE 16–1 General structure of H1-antagonist drugs and examples of the major subgroups. Subgroup names are based on the shaded moieties. these agents, but histamine-stimulated gastric acid secretion and the stimulation of the heart are unaffected.


Pharmacology_Katzung

Pharmacology_Katzung. 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, α adrenoceptor, serotonin, and local anesthetic receptor sites. Some of these actions are of therapeutic value and some are undesirable.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 US Food and Drug Administration (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.


Pharmacology_Katzung

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


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 16–2 Some H1 antihistaminic drugs in clinical use. Promethazine (Phenergan, etc) 10–25 mg +++ Marked sedation; antiemetic; α-block nd, no data found. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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 H1 antagonists 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 overthe-counter generic formulations. B. Motion Sickness and Vestibular Disturbances


Pharmacology_Katzung

Pharmacology_Katzung. 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 H1 antagonists are more effective in preventing motion sickness when combined with ephedrine or amphetamine.


Pharmacology_Katzung

Pharmacology_Katzung. It has been claimed that the antihistaminic agents effective in prophylaxis of motion sickness are also useful in Méniére’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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 peripheral 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 H1and 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).


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 285 FIGURE 16–2 Synthesis of serotonin and melatonin from 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. Telotristat ethyl, an orally active hydroxylase inhibitor, has been approved for the treatment of diarrhea due to carcinoid tumor.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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).


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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. A. Mechanisms of Action


Pharmacology_Katzung

Pharmacology_Katzung. 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 seven-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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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 TABLE 16–3 Serotonin receptor subtypes currently recognized. (See also Chapter 21.) 1Research agents; for chemical names see Alexander SPH, Mathie A, Peters JA: Guide to receptors and channels (GRAC). Br J Pharmacol 2011;164 (Suppl 1):S16–17, 116–117. cAMP, cyclic adenosine monophosphate; EPSP, excitatory postsynaptic potential; IP3, inositol trisphosphate. CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 287


Pharmacology_Katzung

Pharmacology_Katzung. 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 supra-chiasmatic nucleus of the hypothalamus, an area associated— from lesioning experiments—with circadian rhythm. MT1 and 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


Pharmacology_Katzung

Pharmacology_Katzung. 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. Insomnia associated with autism spectrum disorder may respond to melatonin. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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 insom-nia. 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 MT2 agonist 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.


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Pharmacology_Katzung. by chemical triggers such as cancer chemotherapy drugs. 5-HT1P and 5-HT4 receptors also play important roles in enteric nervous system function.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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-HT2B agonists 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.


Pharmacology_Katzung

Pharmacology_Katzung. animal models, many of the signs of the syndrome can be reversed by administration of 5-HT2 antagonists; 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 precipitat-ing drugs are given (see Chapter 27). Excess synaptic serotonin causes a serious, potentially fatal syn-drome 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 patho-physiology and management are


Pharmacology_Katzung

Pharmacology_Katzung. within recent weeks and physical findings. It has some characteristics in common with neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH), but its patho-physiology 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 concur-rent 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


Pharmacology_Katzung

Pharmacology_Katzung. 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 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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-HT2 smooth 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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). 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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. 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 TABLE 16–4 Characteristics of serotonin syndrome and other hyperthermic syndromes. 1Precipitating drugs should be discontinued immediately. First-line therapy is in boldface font. LSD, lysergic acid diethylamide, MAOIs, monoamine oxidase inhibitors; MDMA, methylenedioxy-methamphetamine (ecstasy); SSRIs, selective serotonin reuptake inhibitors. CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 289


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Pharmacology_Katzung. 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 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 obe-sity 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. (Underweight


Pharmacology_Katzung

Pharmacology_Katzung. 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. (Underweight persons, ie, those with a BMI < 18, also have an increased [but smaller] risk of health problems.) Some extremely muscular individuals may have a BMI higher than 25 and no excess fat; however, the BMI scale gener-ally 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; cardiovas-cular risk is lower if this ratio is less than 0.5. Experts consider drug therapy to be justified in patients with increased risk factors and a BMI ≥ 27 and in those without comorbidities but with a BMI ≥ 30. 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


Pharmacology_Katzung

Pharmacology_Katzung. but with a BMI ≥ 30. 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 con-trol is extremely complex, and the pathophysiology of obesity is still poorly understood. Many hormones and neuronal mecha-nisms 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 might appear to offer many targets for weight-reducing drug therapy, but despite intensive research, no available phar-macologic 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 mecha-nisms. In contrast, bariatric (weight-reducing) surgery readily achieves a sustained weight loss


Pharmacology_Katzung

Pharmacology_Katzung. influences that are independent of or only partially dependent on the physiologic control mecha-nisms. 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. Even a 5–10% loss of weight is associated with a reduction in blood pres-sure and improved glycemic control. Gastrointestinal flora also influence metabolic efficiency, and research in mice suggests that altering the microbiome 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-Phen and Dex-Phen, they were moderately effective. However, these 5-HT2 agonists were found to cause pulmo-nary hypertension and cardiac


Pharmacology_Katzung

Pharmacology_Katzung. and dexfenfluramine. Combined with phentermine as Fen-Phen and Dex-Phen, they were moderately effective. However, these 5-HT2 agonists were found to cause pulmo-nary 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. Liraglutide, lorcaserin, orlistat, and phentermine are the only single-agent drugs currently approved in the USA for the treat-ment of obesity. In addition, combination agents (phentermine plus topiramate and naltrexone plus bupropion) are available. These drugs have been intensely studied,


Pharmacology_Katzung

Pharmacology_Katzung. approved in the USA for the treat-ment of obesity. In addition, combination agents (phentermine plus topiramate and naltrexone plus bupropion) are available. These drugs have been intensely studied, and some of their prop-erties are listed in Table 16–5. Clinical trials and phase 4 reports suggest that these 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. Mirabegron, a β3 adrenoceptor agonist approved for the treatment for overactive bladder (see Chapter 9), is of possible future interest because β3 agonists activate brown fat to consume more energy. Sibutramine and rimonabant were marketed for several years but were withdrawn because of increas-ing evidence of cardiovascular and other toxicities. Because of the low efficacy and the toxicity of the available drugs, intensive research continues. Because of the redundancy of the


Pharmacology_Katzung

Pharmacology_Katzung. of increas-ing evidence of cardiovascular and other toxicities. Because of the low efficacy and the toxicity of the available drugs, intensive research continues. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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, a 5-HT2C agonist, is approved by the FDA for use as a weight-loss medication (see Box: Treatment of Obesity).


Pharmacology_Katzung

Pharmacology_Katzung. 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 more than 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 intra-cranial (and possibly extracranial) arteries. These nerves release TABLE 16–5 Antiobesity drugs and their effects.


Pharmacology_Katzung

Pharmacology_Katzung. Migraine involves the trigeminal nerve distribution to intra-cranial (and possibly extracranial) arteries. These nerves release TABLE 16–5 Antiobesity drugs and their effects. Liraglutide GLP-1 agonist Decreases appetite 3 mg/d SC Nausea, vomiting, pancreatitis Lorcaserin 5-HT2c agonist Decreases appetite 10 mg PO BID Headache, nausea, dry mouth, dizziness, constipation Naltrexone/ Opioid antagonist Unknown 32 mg/ Headache, nausea, dizziness, constipation bupropion + antidepressant Phentermine Sympathomimetic Norepinephrine release in CNS 30–37.5 mg/d PO Increased BP, HR; arrhythmias, insomnia, anxiety


Pharmacology_Katzung

Pharmacology_Katzung. Phentermine/ Sympathomimetic Norepinephrine release plus 3.75–15 mg/ Insomnia, dizziness, nausea, paresthesia, topiramate + antiseizure agent unknown mechanism 23–92 mg PO dysgeusia 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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. Sumatriptan and the other triptans are selective agonists Orlistat GI lipase inhibitor Reduces lipid absorption 60–120 mg TID PO Decreased absorption of fat-soluble vitamins, flatulence, fecal incontinence


Pharmacology_Katzung

Pharmacology_Katzung. Orlistat GI lipase inhibitor Reduces lipid absorption 60–120 mg TID PO Decreased absorption of fat-soluble vitamins, flatulence, fecal incontinence In population studies, all of the triptan 5-HT1 agonists are as effective or more effective in migraine than other acute drug treatments, eg, parenteral, oral, and rectal ergot alkaloids. However, individual drugs in this class may have different 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. cent of patients BID, twice daily; BP, blood pressure; CNS, central nervous system; GI, gastrointestinal; HR, heart rate; PO, by mouth; SC, subcutaneously; TID, three times daily. Treatment (P = placebo, S = sumatriptan)


Pharmacology_Katzung

Pharmacology_Katzung. Treatment (P = placebo, S = sumatriptan) 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 for 5-HT1D and 5-HT1B receptors; the similarity of the triptan 1991;265:2831.) TABLE 16–6 Pharmacokinetics of triptans.


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Pharmacology_Katzung. efficacies in individual patients. The pharmacokinetics and potencies 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. Flibanserin, a 5-HT1a agonist and 5-HT2A antagonist, is approved for treatment of hypoactive sexual desire disorder in women. Due to inadequate evidence of efficacy, it was refused approval in 2010 and 2013. The clinical trials that led to its approval in 2015 showed a very small but significant increase in satisfactory sexual desire and activities over several weeks of daily oral administration. Consumption of alcohol is contraindicated due to increased risk of severe hypotension. Other adverse effects include syncope, nausea, fatigue, dizziness, and somnolence. Cisapride, a 5-HT4 agonist, was used in the treatment of gastroesophageal reflux and motility disorders. Because of toxicity, it is now available only for compassionate use in the USA. Tegaserod, a 5-HT4 partial agonist, is used for irritable bowel syndrome with constipation (see Chapter 62).


Pharmacology_Katzung

Pharmacology_Katzung. 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. 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. 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.


Pharmacology_Katzung

Pharmacology_Katzung. A wide variety of drugs with actions at other receptors (eg, α adrenoceptors, H1-histamine receptors) also have serotonin receptor-blocking effects. Phenoxybenzamine (see Chapter 10) has a long-lasting blocking action at 5-HT2 receptors. 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 H1 histamine 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 orally 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 patients, but controlled trials have yielded mixed results.


Pharmacology_Katzung

Pharmacology_Katzung. 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 α1 adrenoceptors. 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 α1 adrenoceptor 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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. 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 α 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 semi-synthetic modifications have yielded a large number of agents of experimental and clinical interest. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 ergotism occurred in the small French village of Pont-Saint-Esprit in 1951. It was vividly 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 symp-toms 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


Pharmacology_Katzung

Pharmacology_Katzung. 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. As noted in the text, epidemics of ergotism, or poisoning by ergot-contaminated grain, are known to have occurred sporadi-cally 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 simultane-ously 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, ergot-ism has not disappeared. A most convincing demonstration of


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 16–7 Major ergoline derivatives (ergot alkaloids). 1Dihydroergotamine lacks the double bond between carbons 9 and 10. 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. A. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. 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 α 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.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 16–8 Effects of ergot alkaloids at several receptors.1 1Agonist effects are indicated by +, antagonist by −, no effect by 0. Relative affinity for the receptor is indicated by the number of + or − signs. PA means partial agonist (both agonist and antagonist effects can be detected). B. Organ System Effects 1.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 α agonists. This dual effect reflects the drug’s partial agonist Percent of maximum 5-HT contraction 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.


Pharmacology_Katzung

Pharmacology_Katzung. Although much of the vasoconstriction elicited by ergot alkaloids can be ascribed to partial agonist effects at α 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 selective 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 α antagonists, serotonin antagonists, or combinations of both.


Pharmacology_Katzung

Pharmacology_Katzung. Ergotamine is typical of the ergot alkaloids that have a strong vasoconstrictor 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 α 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 of the uterus 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 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.) 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.


Pharmacology_Katzung

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


Pharmacology_Katzung

Pharmacology_Katzung. 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, sub-lingual, 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. D. Diagnosis of Variant Angina Ergonovine given intravenously has been used to produce 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-α-ergocryptine and three similar dihydrogenated peptide ergot alkaloids (ergoloid mesylates), has been promoted for many years for the relief of signs of senility and, more recently, for the treatment of Alzheimer’s dementia. There is no useful evidence that this drug has significant benefit.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 non-ergot 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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. H1 ANTIHISTAMINES First generation: Second generation: Competitive antagonism/inverse agonism at H1 receptors Reduces or prevents histamine effects on smooth muscle, Reduces or prevents histamine effects on smooth muscle, immune cells IgE immediate allergies; especially hay fever, urticaria • often used as a sedative, antiemetic, and anti-motion sickness drug IgE immediate allergies; especially hay fever, urticaria Oral and parenteral • duration 4–6 h • Toxicity:


Pharmacology_Katzung

Pharmacology_Katzung. IgE immediate allergies; especially hay fever, urticaria Oral and parenteral • duration 4–6 h • Toxicity: Sedation when used in hay fever, muscarinic blockade symptoms, orthostatic hypotension • Interactions: Additive sedation with other sedatives, including alcohol • some inhibition of CYP2D6, may prolong action of some β blockers Oral • duration 12–24 h • Toxicity: Sedation and arrhythmias in overdose • Interactions: Minimal Other first-generation H1 blockers: Chlorpheniramine is a less sedating H1 blocker with fewer autonomic effects. Doxylamine, a strongly sedating H1 blocker, is available over-the-counter in many sleep-aid formulations and in Diclegis (in combination with pyridoxine) for use in nausea and vomiting of pregnancy Other second-generation H1 blockers: Loratadine, desloratadine, and fexofenadine are very similar to cetirizine H2 ANTIHISTAMINES •Cimetidine,others(seeChapter62) Oral, nasal, parenteral • duration 2 h • Toxicity:


Pharmacology_Katzung

Pharmacology_Katzung. H2 ANTIHISTAMINES •Cimetidine,others(seeChapter62) Oral, nasal, parenteral • duration 2 h • Toxicity: Paresthesias, dizziness, coronary vasoconstriction • Interactions: Additive with other vasoconstrictors • Other triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan): Similar to sumatriptan except for pharmacokinetics (2–6 h duration of action); much more expensive than generic sumatriptan


Pharmacology_Katzung

Pharmacology_Katzung. Subclass, Drug Mechanism of Action Effects Clinical Applications Pharmacokinetics, Toxicities, Interactions SEROTONIN BLOCKERS 5-HT2: 5-HT3: • Ondansetron, others (see Chapter 62) •ErgotamineMixed partial agonist effects at 5-HT2 and α adrenoceptors Causes marked smooth muscle contraction but blocks α-agonist vasoconstriction Migraine and cluster headache Oral,parenteral•duration12–24h•Toxicity: Prolonged vasospasm causing angina, gangrene; uterine spasm Uteroselective: •ErgonovineMixed partial agonist effects at 5-HT2 and α adrenoceptors Sameasergotamine•someselectivity for uterine smooth muscle Postpartum bleeding •migraineheadacheOral,parenteral(methylergonovine)•duration2–4h•Toxicity: Same as ergotamine CNS selective: •Lysergicaciddiethylamide Central nervous system 5-HT2 and dopamine agonist •5-HT2 antagonist in periphery Hallucinations •psychotomimeticNone•widelyabused Oral•durationseveralhours•Toxicity: Prolonged psychotic state, flashbacks • Bromocriptine, pergolide: Ergot


Pharmacology_Katzung

Pharmacology_Katzung. agonist •5-HT2 antagonist in periphery Hallucinations •psychotomimeticNone•widelyabused Oral•durationseveralhours•Toxicity: Prolonged psychotic state, flashbacks • Bromocriptine, pergolide: Ergot derivatives used in Parkinson’s disease (see Chapter 28) and prolactinoma (see Chapter 37). Pergolide used in equine Cushing’s disease


Pharmacology_Katzung

Pharmacology_Katzung. Azelastine Generic, Astelin (nasal), Optivar (ophthalmic) Brompheniramine Brovex, Dimetapp, others Carbinoxamine Generic, Histex Cetirizine Generic, Zyrtec Chlorpheniramine Generic, Chlor-Trimeton Clemastine Generic, Tavist Cyclizine Generic, Marezine Cyproheptadine Generic, Periactin Desloratadine Generic, Clarinex Dimenhydrinate† Generic, Dramamine Diphenhydramine Generic, Benadryl Doxylamine Diclegis (combination with pyridoxine), Unisom Sleep Tabs Fexofenadine Generic, Allegra Hydroxyzine Generic, Vistaril Ketotifen Generic, Zaditor Levocetirizine Generic, Xyzal Loratadine Generic, Claritin Meclizine Generic, Antivert, Bonine Olopatadine Patanol, Pataday Promethazine Generic, Phenergan Triprolidine Generic, Zymine, Tripohist Epinastine Generic, Elestat


Pharmacology_Katzung

Pharmacology_Katzung. Meclizine Generic, Antivert, Bonine Olopatadine Patanol, Pataday Promethazine Generic, Phenergan Triprolidine Generic, Zymine, Tripohist Epinastine Generic, Elestat GENERIC NAME AVAILABLE AS Flibanserin Addyi Frovatriptan Frova Naratriptan Generic, Amerge Rizatriptan Generic, Maxalt, Maxalt-MLT Sumatriptan Generic, Imitrex Zolmitriptan Generic, Zomig 5-HT ANTAGONISTS See Chapter 62. MELATONIN RECEPTOR AGONISTS Ramelteon Rozarem Tasimelteon Hetlioz ERGOT ALKALOIDS Dihydroergotamine Generic, Migranal, D.H.E. 45 Methylergonovine Generic, Methergine ANTIOBESITY DRUGS GENERIC NAME AVAILABLE AS Ergonovine Generic, Ergotrate Ergotamine mixtures (include caffeine) Generic, Cafergot Ergotamine tartra Generic, Ergomar Liraglutide Saxenda, Victoza Lorcaserin Belviq Naltrexone/bupropion Contrave Orlistat Alli, Xenical Phentermine Generic, Adipex-P, Lomaira Phentermine/topiramate Qsymia *Several other antihistamines are available only in combination products with, for example, phenylephrine.