Katzung - Autacoids

SECTION IV DRUGS WITH IMPORTANT ACTIONS ON
SMOOTH MUSCLE
16
C H A P T E R
Histamine, Serotonin,
& the Ergot Alkaloids
Bertram G. Katzung, MD, PhD
C ASE STUDY
A healthy 45-year-old physician attending a reunion in a signs and symptoms with marked orthostatic hypotension.
vacation hotel developed dizziness, redness of the skin over The menu included a green salad, sautéed fish with rice, and
the head and chest, and tachycardia while eating. A short apple pie. What is the probable diagnosis? How would you
time later, another physician at the table developed similar treat these patients?
It has long been known that many tissues contain substances Because of their broad and largely undesirable peripheral
that, when released by various stimuli, cause physiologic effects effects, neither histamine nor serotonin has any clinical applica-
such as reddening of the skin, pain or itching, and broncho- tion in the treatment of disease. However, compounds that
spasm. Later, it was discovered that many of these substances selectively activate certain receptor subtypes or selectively antago-
are also present in nervous tissue and have multiple functions. nize the actions of these amines are of considerable clinical value.
Histamine and serotonin (5-hydroxytryptamine, 5-HT) are bio- This chapter therefore emphasizes the basic pharmacology of the
logically active amines that function as neurotransmitters and are agonist amines and the clinical pharmacology of the more selective
also found in non-neural tissues, have complex physiologic and agonist and antagonist drugs. Obesity, a poorly understood condi-
pathologic effects through multiple receptor subtypes, and are tion, appears to involve many receptors, including some histamine
often released locally. Together with endogenous peptides (see and serotonin receptors. It is discussed in a special section following
Chapter 17), prostaglandins and leukotrienes (see Chapter 18), the discussion of serotonin and its antagonists. The ergot alkaloids,
and cytokines (see Chapter 55), they constitute the autacoid compounds with partial agonist activity at serotonin and several
group of drugs. other receptors, are discussed at the end of the chapter.
277
278 SECTION IV Drugs with Important Actions on Smooth Muscle
■■ HISTAMINE of the stomach. ECL cells release histamine, one of the primary
gastric acid secretagogues, to activate the acid-producing parietal
Histamine was synthesized in 1907 and later isolated from cells of the mucosa (see Chapter 62).
mammalian tissues. Early hypotheses concerning the possible
physiologic roles of tissue histamine were based on similarities Storage & Release of Histamine
between the effects of intravenously administered histamine and
The stores of histamine in mast cells can be released through
the symptoms of anaphylactic shock and tissue injury. Marked
several mechanisms.
species variation is observed, but in humans histamine is an
important mediator of immediate allergic (such as urticaria) and
A. Immunologic Release
inflammatory reactions, although it plays only a modest role in
anaphylaxis. Histamine plays an important role in gastric acid Immunologic processes account for the most important patho-
secretion (see Chapter 62) and functions as a neurotransmitter physiologic mechanism of mast cell and basophil histamine
and neuromodulator (see Chapters 6 and 21). Newer evidence release. These cells, if sensitized by IgE antibodies attached
indicates that histamine also plays a role in immune functions and to their surface membranes, degranulate explosively when
chemotaxis of white blood cells. 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,
BASIC PHARMACOLOGY OF HISTAMINE adenosine triphosphate (ATP), and other mediators that are
stored together in the granules. Histamine released by this
Chemistry & Pharmacokinetics mechanism is a mediator in immediate (type I) allergic reac-
tions, such as hay fever and acute urticaria. Substances released
Histamine occurs in plants as well as in animal tissues and is a
during IgG- or IgM-mediated immune reactions that activate
component of some venoms and stinging secretions.
the complement cascade also release histamine from mast cells
Histamine is formed by decarboxylation of the amino acid
and basophils.
l-histidine, a reaction catalyzed in mammalian tissues by the
By a negative feedback control mechanism mediated by H2
enzyme histidine decarboxylase. Once formed, histamine is either
receptors, histamine appears to modulate its own release and that
stored or rapidly inactivated. Very little histamine is excreted
of other mediators from sensitized mast cells in some tissues.
unchanged. The major metabolic pathways involve conversion to
In humans, mast cells in skin and basophils show this negative
N-methylhistamine, methylimidazoleacetic acid, and imidazoleacetic
feedback mechanism; lung mast cells do not. Thus, histamine
acid (IAA). Certain neoplasms (systemic mastocytosis, urticaria pig-
may act to limit the intensity of the allergic reaction in the skin
mentosa, gastric carcinoid, and occasionally myelogenous leukemia)
and blood.
are associated with increased numbers of mast cells or basophils and
Endogenous histamine has a modulating role in a variety of
with increased excretion of histamine and its metabolites.
inflammatory and immune responses. Upon injury to a tissue,
released histamine causes local vasodilation and leakage of
CH2 CH2 NH2
plasma-containing mediators of acute inflammation (comple-
HN N ment, C-reactive protein) and antibodies. Histamine has an
active chemotactic attraction for inflammatory cells (neutrophils,
Histamine eosinophils, basophils, monocytes, and lymphocytes). Histamine
inhibits the release of lysosome contents and several T- and
Most tissue histamine is sequestered and bound in granules B-lymphocyte functions. Most of these actions are mediated by
(vesicles) in mast cells or basophils; the histamine content of H2 or H4 receptors. Release of peptides from nerves in response to
many tissues is directly related to their mast cell content. The inflammation is also probably modulated by histamine acting on
bound form of histamine is biologically inactive, but as noted presynaptic H3 receptors.
below, many stimuli can trigger the release of mast cell histamine,
allowing the free amine to exert its actions on surrounding tissues. B. Chemical and Mechanical Release
Mast cells are especially rich at sites of potential tissue injury— Certain amines, including drugs such as morphine and tubocu-
nose, mouth, and feet; internal body surfaces; and blood vessels, rarine, can displace histamine from its bound form within cells.
particularly at pressure points and bifurcations. This type of release does not require energy and is not associ-
Non-mast cell histamine is found in several tissues, includ- ated with mast cell injury or explosive degranulation. Loss of
ing the brain, where it functions as a neurotransmitter. Strong granules from the mast cell also releases histamine, because
evidence implicates endogenous neurotransmitter histamine in sodium ions in the extracellular fluid rapidly displace the
many brain functions such as neuroendocrine control, cardio amine from the complex. Chemical and mechanical mast cell
vascular regulation, thermal and body weight regulation, and sleep injury causes degranulation and histamine release. Compound
and arousal (see Chapter 21). 48/80, an experimental drug, selectively releases histamine
A second important nonneuronal site of histamine storage from tissue mast cells by an exocytotic degranulation process
and release is the enterochromaffin-like (ECL) cells of the fundus requiring energy and calcium.
CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 279
Pharmacodynamics chemotactic effects on eosinophils and mast cells. In this role, they
seem to play a part in inflammation and allergy. They may also
A. Mechanism of Action
modulate production of these cell types and they may mediate, in
Histamine exerts its biologic actions by combining with specific part, the previously recognized effects of histamine on cytokine
receptors located on the cell membrane. Four different histamine production.
receptors have been characterized and are designated H1–H4; they
are described in Table 16–1. Unlike the other amine transmitter B. Tissue and Organ System Effects of Histamine
receptors discussed previously, no subfamilies have been found Histamine exerts powerful effects on smooth and cardiac muscle,
within these major types, although different splice variants of on certain endothelial and nerve cells, on the secretory cells of
several receptor types have been described. the stomach, and on inflammatory cells. However, sensitivity to
All four receptor types have been cloned and belong to the histamine varies greatly among species. Guinea pigs are exquisitely
large superfamily of G protein-coupled receptors (GPCR). The sensitive; humans, dogs, and cats somewhat less so; and mice and
structures of the H1 and H2 receptors differ significantly and rats very much less so.
appear to be more closely related to muscarinic and 5-HT1
receptors, respectively, than to each other. The H4 receptor has 1. Nervous system—Histamine is a powerful stimulant of
about 40% homology with the H3 receptor but does not seem sensory nerve endings, especially those mediating pain and
to be closely related to any other histamine receptor. All four itching. This H1-mediated effect is an important component of
histamine receptors have been shown to have constitutive activity the urticarial response and reactions to insect and nettle stings.
in some systems; thus, some antihistamines previously considered to Some evidence suggests that local high concentrations can also
be traditional pharmacologic antagonists must now be considered depolarize efferent (axonal) nerve endings (see Triple Response,
to be inverse agonists (see Chapters 1 and 2). Indeed, many first- item 8 in this list). In the mouse, and probably in humans, respi-
and second-generation H1 blockers function as inverse agonists. ratory neurons signaling inspiration and expiration are modulated
Furthermore, a single molecule may be an agonist at one hista- by H1 receptors. H1 and H3 receptors play important roles in
mine receptor and an antagonist or inverse agonist at another. For appetite and satiety; antipsychotic drugs that block these receptors
example, clobenpropit, an agonist at H4 receptors, is an antagonist cause significant weight gain (see Chapter 29). These receptors
or inverse agonist at H3 receptors (Table 16–1). may also participate in nociception. Presynaptic H3 receptors play
In the brain, H1 and H2 receptors are located on postsynaptic important roles in modulating release of several transmitters in
membranes, whereas H3 receptors are predominantly presynaptic. the nervous system. H3 agonists reduce the release of acetylcho-
Activation of H1 receptors, which are present in endothelium, line, amine, and peptide transmitters in various areas of the brain
smooth muscle cells, and nerve endings, usually elicits an increase and in peripheral nerves. An investigational inverse H3 agonist,
in phosphoinositol hydrolysis and an increase in inositol trispho- pitolisant (BF2649), appears to reduce drowsiness in patients
sphate (IP3) and intracellular calcium. Activation of H2 receptors, with narcolepsy.
present in gastric mucosa, cardiac muscle cells, and some immune
cells, increases intracellular cyclic adenosine monophosphate 2. Cardiovascular system—In humans, injection or infusion
(cAMP) via Gs. Like the β2 adrenoceptor, under certain circum- of histamine causes a decrease in systolic and diastolic blood pres-
stances the H2 receptor may couple to Gq, activating the IP3-DAG sure and an increase in heart rate. The blood pressure changes are
(inositol 1,4,5-trisphosphate-diacylglycerol) cascade. Activation caused by the vasodilator action of histamine on arterioles and
of H3 receptors decreases transmitter release from histaminergic precapillary sphincters; the increase in heart rate involves both
and other neurons, probably mediated by a decrease in calcium stimulatory actions of histamine on the heart and a reflex tachy-
influx through N-type calcium channels in nerve endings. H4 cardia. Flushing, a sense of warmth, and headache may also occur
receptors are found mainly on leukocytes in the bone marrow during histamine administration, consistent with the vasodila-
and circulating blood. H4 receptors appear to have very important tion. Vasodilation elicited by small doses of histamine is caused
TABLE 16–1 Histamine receptor subtypes.

Receptor Postreceptor Partially Selective Partially Selective Antagonists or
Subtype Distribution Mechanism Agonists Inverse Agonists
1
H1 Smooth muscle, endothelium, brain Gq, ↑ IP3, DAG Histaprodifen Mepyramine, triprolidine, cetirizine
1 1
H2 Gastric mucosa, cardiac muscle, mast cells, brain Gs, ↑ cAMP Amthamine Cimetidine, ranitidine, tiotidine
1
H3 Presynaptic autoreceptors and heteroreceptors: Gi, ↓ cAMP R-α-Methylhistamine, Thioperamide, iodophenpropit,
brain, myenteric plexus, other neurons imetit, immepip clobenpropit,1 tiprolisant,1 proxyfan
1
H4 Eosinophils, neutrophils, CD4 T cells Gi, ↓ cAMP Clobenpropit, imetit, Thioperamide
clozapine
1
Inverse agonist.
cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol trisphosphate.
by H1-receptor activation and is mediated mainly by release of genitourinary tract. However, pregnant women suffering
nitric oxide from the endothelium (see Chapter 19). The decrease anaphylactic reactions may abort as a result of histamine-
in blood pressure is usually accompanied by a reflex tachycardia. induced contractions, and in some species the sensitivity of the
Higher doses of histamine activate the H2-mediated cAMP process uterus is sufficient to form the basis for a bioassay.
of vasodilation and direct cardiac stimulation. In humans, the 4. Secretory tissue—Histamine has long been recognized as a
cardiovascular effects of small doses of histamine can usually be powerful stimulant of gastric acid secretion and, to a lesser
antagonized by H1-receptor antagonists alone. extent, of gastric pepsin and intrinsic factor production. The
Histamine-induced edema results from the action of the effect is caused by activation of H2 receptors on gastric parietal
amine on H1 receptors in the vessels of the microcirculation, cells and is associated with increased adenylyl cyclase activity,
especially the postcapillary vessels. The effect is associated cAMP concentration, and intracellular Ca2+ concentration.
with the separation of the endothelial cells, which permits Other stimulants of gastric acid secretion such as acetylcholine
the transudation of fluid and molecules as large as small and gastrin do not increase cAMP even though their maximal
proteins into the perivascular tissue. This effect is responsible effects on acid output can be reduced—but not abolished—by
for urticaria (hives), which signals the release of histamine in H2-receptor antagonists. These actions are discussed in more
the skin. Studies of endothelial cells suggest that actin and detail in Chapter 62. Histamine also stimulates secretion in the
myosin within these cells cause contraction, resulting in separa- small and large intestine. In contrast, H3-selective histamine
tion of the endothelial cells and increased permeability. agonists inhibit acid secretion stimulated by food or pentagas-
Direct cardiac effects of histamine include both increased trin in several species.
contractility and increased pacemaker rate. These effects are Histamine has much smaller effects on the activity of
mediated chiefly by H2 receptors. In human atrial muscle, other glandular tissue at ordinary concentrations. Very high
histamine can also decrease contractility; this effect is medi- concentrations can cause catecholamine release from the
ated by H1 receptors. The physiologic significance of these adrenal medulla.
cardiac actions is not clear. Some of the cardiovascular signs 5. Metabolic effects—Recent studies of H3-receptor knockout
and symptoms of anaphylaxis are due to released histamine, mice demonstrate that absence of this receptor results in
although several other mediators are involved and are much increased food intake, decreased energy expenditure, and
more important than histamine in humans. obesity. They also show insulin resistance and increased blood
1. Bronchiolar smooth muscle—In both humans and guinea levels of leptin and insulin. It is not yet known whether the
pigs, histamine causes bronchoconstriction mediated by H3 receptor has a similar role in humans, but research is under
H1 receptors. In the guinea pig, this effect is the cause of death way to determine whether H3 agonists are useful in the
from histamine toxicity, but in humans with normal airways, treatment of obesity.
bronchoconstriction following small doses of histamine is not 6. The “triple response”—Intradermal injection of histamine
marked. However, patients with asthma are very sensitive to causes a characteristic red spot, edema, and flare response. The
histamine. The bronchoconstriction induced in these patients effect involves three separate cell types: smooth muscle in the
probably represents a hyperactive neural response, since such microcirculation, capillary or venular endothelium, and
patients also respond excessively to many other stimuli, and the sensory nerve endings. At the site of injection, a reddening
response to histamine can be blocked by autonomic block- appears owing to dilation of small vessels, followed soon by an
ing drugs such as ganglion blocking agents as well as by edematous wheal at the injection site and a red irregular flare
H1-receptor antagonists (see Chapter 20). Although methacho- surrounding the wheal. The flare is said to be caused by an axon
line provocation is more commonly used, tests using small reflex. A sensation of itching may accompany these effects.
doses of inhaled histamine have been used in the diagnosis of Similar local effects may be produced by injecting histamine
bronchial hyperreactivity in patients with suspected asthma or liberators (compound 48/80, morphine, etc) intradermally or
cystic fibrosis. Such individuals may be 100 to 1000 times by applying the appropriate antigens to the skin of a sensitized
more sensitive to histamine (and methacholine) than are person. Although most of these local effects can be prevented
normal subjects. Curiously, a few species (eg, rabbit) respond by adequate doses of an H1-receptor-blocking agent, H2 and
to histamine with bronchodilation, reflecting the dominance of H3 receptors may also be involved.
the H2 receptor in their airways.
7. Other effects possibly mediated by histamine receptors—
2. Gastrointestinal tract smooth muscle—Histamine causes In addition to the local stimulation of peripheral pain nerve
contraction of intestinal smooth muscle, and histamine- endings via H3 and H1 receptors, histamine may play a role
induced contraction of guinea pig ileum is a standard bioassay in nociception in the central nervous system. Burimamide, an
for this amine. The human gut is not as sensitive as that of the early candidate for H2-blocking action, and newer analogs with
guinea pig, but large doses of histamine may cause diarrhea, no notable effect on H1, H2, or H3 receptors, have been shown
partly as a result of this effect. This action of histamine is to have significant analgesic action in rodents when adminis-
mediated by H1 receptors. tered into the central nervous system. The analgesia is said to be
3. Other smooth muscle organs—In humans, histamine generally comparable to that produced by opioids, but tolerance, respira-
has insignificant effects on the smooth muscle of the eye and tory depression, and constipation have not been reported.
Other Histamine Agonists ■■ HISTAMINE RECEPTOR

Small substitutions on the imidazole ring of histamine signifi- ANTAGONISTS
cantly modify the selectivity of the compounds for the histamine
receptor subtypes. Some of these are listed in Table 16–1.
H1-RECEPTOR ANTAGONISTS
Compounds that competitively block histamine or act as inverse
CLINICAL PHARMACOLOGY OF agonists at H1 receptors have been used in the treatment of allergic
HISTAMINE conditions for many years, and in the discussion that follows are
referred to as antagonists. Many H1 antagonists are currently
Clinical Uses marketed in the USA. A large number are available without
prescription, both alone and in combination formulations such as
In pulmonary function laboratories, histamine aerosol has rarely “cold pills” and “sleep aids” (see Chapter 63).
been used as a provocative test of bronchial hyperreactivity.
Histamine has no other current clinical applications.
BASIC PHARMACOLOGY OF
Toxicity & Contraindications H1-RECEPTOR ANTAGONISTS
Adverse effects of histamine release, like those following admin-
istration of histamine, are dose related. Flushing, hypotension, Chemistry & Pharmacokinetics
tachycardia, headache, urticaria, bronchoconstriction, and The H1 antagonists are conveniently divided into first-generation
gastrointestinal upset are noted. These effects are also observed after and second-generation agents. These groups are distinguished by
the ingestion of spoiled fish (scombroid fish poisoning), and the relatively strong sedative effects of most of the first-generation
histamine produced by bacterial action in the flesh of improperly drugs. The first-generation agents are also more likely to block
stored fish is the major causative agent. autonomic receptors. Second-generation H1 blockers are less
Histamine should not be given to patients with asthma (except sedating, owing in part to reduced distribution into the central
as part of a carefully monitored test of pulmonary function) or to nervous system. All the H1 antagonists are stable amines with
patients with active ulcer disease or gastrointestinal bleeding. the general structure illustrated in Figure 16–1. Doses of some of
these drugs are given in Table 16–2.
These agents are rapidly absorbed after oral administration,
HISTAMINE ANTAGONISTS with peak blood concentrations occurring in 1–2 hours. They are
widely distributed throughout the body, and the first-generation
The effects of histamine released in the body can be reduced in H1 blockers enter the central nervous system readily. Some of them
several ways. Physiologic antagonists, especially epinephrine, are extensively metabolized, primarily by microsomal systems in
have smooth muscle actions opposite to those of histamine, but the liver. Several of the second-generation agents are metabolized
they act at different receptors. This is important clinically because by the CYP3A4 system and thus are subject to important interac-
injection of epinephrine can be lifesaving in systemic anaphylaxis tions when other drugs (such as ketoconazole) inhibit this subtype
and in other conditions in which massive release of histamine— of P450 enzymes. Most of the drugs have an effective duration
and other more important mediators—occurs. of action of 4–6 hours following a single dose, but meclizine and
Release inhibitors reduce the degranulation of mast cells that several second-generation agents are longer-acting, with a dura-
results from immunologic triggering by antigen-IgE interaction. tion of action of 12–24 hours. The newer agents are considerably
Cromolyn and nedocromil appear to have this effect (see less lipid-soluble than the first-generation drugs and are substrates
Chapter 20) and have been used in the treatment of asthma. of the P-glycoprotein transporter in the blood-brain barrier; as a
Beta2-adrenoceptor agonists also appear capable of reducing result, they enter the central nervous system with difficulty or not
histamine release. at all. Many H1 antagonists have active metabolites. The active
Histamine receptor antagonists represent a third approach to metabolites of hydroxyzine, terfenadine, and loratadine are available
the reduction of histamine-mediated responses. For over 70 years, as drugs (cetirizine, fexofenadine, and desloratadine, respectively).
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 Pharmacodynamics
in 1972 was it possible to antagonize the gastric acid-stimulating Both neutral H1 antagonists and inverse H1 agonists reduce or
activity of histamine. The development of selective H2-receptor block the actions of histamine by reversible competitive binding to
antagonists has led to more effective therapy for peptic disease (see the H1 receptor. Several have been clearly shown to be inverse ago-
Chapter 62). Selective H3 and H4 antagonists are not yet available nists, and it is possible that all act by this mechanism. They have
for clinical use. However, potent and partially selective experimental negligible potency at the H2 receptor and little at the H3 receptor.
H 3-receptor antagonists, thioperamide and clobenpropit, For example, histamine-induced contraction of bronchiolar or
have been developed. gastrointestinal smooth muscle can be completely blocked by
General structure Ethers or ethanolamine derivative
CH3
CH O CH2 CH2 N
X Y C C N
CH3
X is: C or N
Y is: C, O, or omitted Diphenhydramine or dimenhydrinate
Alkylamine derivative Piperidine derivative
CI CH3 OH
CH CH2 CH2 N C
CH3
N
Chlorpheniramine N OH CH3
CH2 CH2 CH2 CH C COOH
CH3
Fexofenadine
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 doxylamine (in Bendectin), were used widely in the past in the
the stimulation of the heart are unaffected. treatment of nausea and vomiting of pregnancy (see below). Although
The first-generation H1-receptor antagonists have many actions Bendectin was withdrawn in 1983, a similar formulation, combining
in addition to blockade of the actions of histamine. The large doxylamine and pyridoxine (Diclegis), was approved by the US Food
number of these actions probably results from the similarity of the and Drug Administration (FDA) in 2013.
general structure (Figure 16–1) to the structure of drugs that have
effects at muscarinic cholinoceptor, α adrenoceptor, serotonin, 3. Antiparkinsonism effects—Some of the H1 antagonists,
and local anesthetic receptor sites. Some of these actions are of especially diphenhydramine, have significant acute suppressant
therapeutic value and some are undesirable. effects on the extrapyramidal symptoms associated with certain
antipsychotic drugs. This drug is given parenterally for acute
1. Sedation—A common effect of first-generation H1 antagonists dystonic reactions to antipsychotics.
is sedation, but the intensity of this effect varies among chemical
subgroups (Table 16–2) and among patients as well. The effect is 4. Antimuscarinic actions—Many first-generation agents,
sufficiently prominent with some agents to make them useful as especially those of the ethanolamine and ethylenediamine sub-
“sleep aids” (see Chapter 63) and unsuitable for daytime use. The groups, have significant atropine-like effects on peripheral mus-
effect resembles that of some antimuscarinic drugs and is considered carinic receptors. This action may be responsible for some of the
very different from the disinhibited sedation produced by sedative- (uncertain) benefits reported for nonallergic rhinorrhea but may
hypnotic drugs. Compulsive use has not been reported. At ordinary also cause urinary retention and blurred vision.
dosages, children occasionally (and adults rarely) manifest excitation
rather than sedation. At very high toxic dose levels, marked stimu- 5. Adrenoceptor-blocking actions—Alpha-receptor-blocking
lation, agitation, and even seizures may precede coma. Second- effects can be demonstrated for many H1 antagonists, especially
generation H1 antagonists have little or no sedative or stimulant those in the phenothiazine subgroup, eg, promethazine. This
actions. These drugs (or their active metabolites) also have far fewer action may cause orthostatic hypotension in susceptible indi-
autonomic effects than the first-generation antihistamines. viduals. Beta-receptor blockade is not significant.
2. Antinausea and antiemetic actions—Several first-generation 6. Serotonin-blocking actions—Strong blocking effects at

H1 antagonists have significant activity in preventing motion sick- serotonin receptors have been demonstrated for some first-
ness (Table 16–2). They are less effective against an episode of generation H1 antagonists, notably cyproheptadine. This drug
motion sickness already present. Certain H1 antagonists, notably is promoted as an antiserotonin agent and is discussed with that
TABLE 16–2 Some H1 antihistaminic drugs in clinical use.

Drugs Usual Adult Dose Anticholinergic Activity Comments
FIRST-GENERATION ANTIHISTAMINES
Ethanolamines
Carbinoxamine (Clistin) 4–8 mg +++ Slight to moderate sedation
Dimenhydrinate (salt of 50 mg +++ Marked sedation; anti-motion sickness activity
diphenhydramine) (Dramamine)
Diphenhydramine (Benadryl, etc) 25–50 mg +++ Marked sedation; anti-motion sickness activity
Piperazine derivatives
Hydroxyzine (Atarax, etc) 15–100 mg nd Marked sedation
Cyclizine (Marezine) 25–50 mg — Slight sedation; anti-motion sickness activity
Meclizine (Bonine, etc) 25–50 mg — Slight sedation; anti-motion sickness activity
Alkylamines
Brompheniramine (Dimetane, etc) 4–8 mg + Slight sedation
Chlorpheniramine (Chlor-Trimeton, 4–8 mg + Slight sedation; common component of OTC “cold”
etc) medication
Phenothiazine derivative
Promethazine (Phenergan, etc) 10–25 mg +++ Marked sedation; antiemetic; a-block
Miscellaneous
Cyproheptadine (Periactin, etc) 4 mg + Moderate sedation; significant antiserotonin activity;
mixed evidence for use as an appetite stimulant
SECOND-GENERATION ANTIHISTAMINES
Piperidine
Fexofenadine (Allegra, etc) 60 mg —
Miscellaneous
Loratadine (Claritin, etc), 10 mg (desloratadine, — Longer action; used at 5 mg dosage
desloratadine (Clarinex) 5 mg)
Cetirizine (Zyrtec, etc) 5–10 mg —
nd, no data found.
drug group. Nevertheless, its structure resembles that of the pheno- CLINICAL PHARMACOLOGY OF
thiazine 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 excit- Clinical Uses
able membranes in the same fashion as procaine and lidocaine. First-generation H1-receptor blockers are still commonly used
Diphenhydramine and promethazine are actually more potent over-the-counter drugs. The prevalence of allergic conditions
than procaine as local anesthetics. They are occasionally used to and the relative safety of the drugs contribute to this heavy use.
produce local anesthesia in patients allergic to conventional local However, the fact that they do cause sedation contributes to heavy
anesthetic drugs. A small number of these agents also block potas- prescribing as well as over-the-counter use of second-generation
sium channels; this action is discussed below (see Toxicity). antihistamines.
8. Other actions—Certain H1 antagonists, eg, cetirizine, inhibit

mast cell release of histamine and some other mediators of inflam- A. Allergic Reactions
mation. This action is not due to H1-receptor blockade and may The H1 antihistaminic agents are often the first drugs used to
reflect an H4-receptor effect (see below). The mechanism is not prevent or treat the symptoms of allergic reactions. In allergic
fully understood but could play a role in the beneficial effects of rhinitis (hay fever), the H1 antagonists are second-line drugs
these drugs in the treatment of allergies such as rhinitis. A few after glucocorticoids administered by nasal spray. In urticaria, in
H1 antagonists (eg, terfenadine, acrivastine) have been shown to which histamine is the primary mediator, the H1 antagonists are
inhibit the P-glycoprotein transporter found in cancer cells, the the drugs of choice and are often quite effective if given before
epithelium of the gut, and the capillaries of the brain. The signifi- exposure. However, in bronchial asthma, which involves several
cance of this effect is not known. mediators, the H1 antagonists are largely ineffective.
Angioedema may be precipitated by histamine release but Toxicity

appears to be maintained by peptide kinins that are not affected by
The wide spectrum of nonantihistaminic effects of the
antihistaminic agents. For atopic dermatitis, antihistaminic drugs
H1 antihistamines is described above. Several of these effects
such as diphenhydramine are used mostly for their sedative side
(sedation, antimuscarinic action) have been used for thera-
effect, which reduces awareness of itching.
peutic purposes, especially in over-the-counter remedies (see
The H1 antihistamines used for treating allergic conditions
Chapter 63). Nevertheless, these two effects constitute the
such as hay fever are usually selected with the goal of minimiz-
most common undesirable actions when these drugs are used
ing sedative effects; in the USA, the drugs in widest use are
to block peripheral histamine receptors.
the alkylamines and the second-generation nonsedating agents.
Less common toxic effects of systemic use include excitation
However, the sedative effect and the therapeutic efficacy of differ-
and convulsions in children, postural hypotension, and allergic
ent agents vary widely among individuals. In addition, the clinical
responses. Drug allergy is relatively common after topical use
effectiveness of one group may diminish with continued use, and
of H1 antagonists. The effects of severe systemic overdosage of
switching to another group may restore drug effectiveness for as
the older agents resemble those of atropine overdosage and are
yet unexplained reasons.
treated in the same way (see Chapters 8 and 58). Overdosage of
The second-generation H1 antagonists are used mainly for
astemizole or terfenadine may induce cardiac arrhythmias; the
the treatment of allergic rhinitis and chronic urticaria. Several
same effect may be caused at normal dosage by interaction with
double-blind comparisons with older agents (eg, chlorpheniramine)
enzyme inhibitors (see Drug Interactions). These drugs are no
indicated about equal therapeutic efficacy. However, sedation
longer marketed in the USA.
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 Drug Interactions
agents. The newer drugs are much more expensive, even in over- Lethal ventricular arrhythmias occurred in several patients taking
the-counter generic formulations. either of the early second-generation agents, terfenadine or
astemizole, in combination with ketoconazole, itraconazole, or
B. Motion Sickness and Vestibular Disturbances macrolide antibiotics such as erythromycin. These antimicrobial
Scopolamine (see Chapter 8) and certain first-generation drugs inhibit the metabolism of many drugs by CYP3A4 and
H1 antagonists are the most effective agents available for the cause significant increases in blood concentrations of the anti-
prevention of motion sickness. The antihistaminic drugs with the histamines. The mechanism of this toxicity involves blockade of
greatest effectiveness in this application are diphenhydramine and the HERG (IKr) potassium channels in the heart that contribute
promethazine. Dimenhydrinate, which is promoted almost exclu- to repolarization of the action potential (see Chapter 14). The
sively for the treatment of motion sickness, is a salt of diphen- result is prolongation and a change in shape of the action poten-
hydramine and has similar efficacy. The piperazines (cyclizine tial, and these changes lead to arrhythmias. Both terfenadine and
and meclizine) also have significant activity in preventing motion astemizole were withdrawn from the US market in recognition of
sickness and are less sedating than diphenhydramine in most these problems. Where still available, terfenadine and astemizole
patients. Dosage is the same as that recommended for allergic should be considered to be contraindicated in patients taking
disorders (Table 16–2). Both scopolamine and the H1 antagonists ketoconazole, itraconazole, or macrolides and in patients with
are more effective in preventing motion sickness when combined liver disease. Grapefruit juice also inhibits CYP3A4 and has been
with ephedrine or amphetamine. shown to increase blood levels of terfenadine significantly.
It has been claimed that the antihistaminic agents effective For those H1 antagonists that cause significant sedation,
in prophylaxis of motion sickness are also useful in Méniére’s concurrent use of other drugs that cause central nervous system
syndrome, but efficacy in the latter condition is not established. 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 antimus-
C. Nausea and Vomiting of Pregnancy carinic and α-blocking drugs.
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 The development of H2-receptor antagonists was based on the
H1 antagonist, was promoted for this application as a component of observation that H1 antagonists had no effect on histamine-
Bendectin, a prescription medication that also contained pyridox- induced acid secretion in the stomach. Molecular manipulation of
ine. Possible teratogenic effects of doxylamine were widely publi- the histamine molecule resulted in drugs that blocked acid secre-
cized in the lay press after 1978 as a result of a few case reports tion and had no H1 agonist or antagonist effects. Like the other
of fetal malformation that occurred after maternal ingestion of histamine receptors, the H2 receptor displays constitutive activity,
Bendectin. However, several large prospective studies disclosed no and some H2 blockers are inverse agonists.
increase in the incidence of birth defects, thereby justifying the The high prevalence of peptic ulcer disease created great interest
reintroduction of a similar product. 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 CH2 NH3+
CH
toxicity has made them extremely popular as over-the-counter prep- COO–
arations. These drugs are discussed in more detail in Chapter 62.
N
H
H3- & H4-RECEPTOR ANTAGONISTS L-tryptophan
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,
HO CH2 NH2
narcolepsy, obesity, and cognitive and psychiatric disorders. CH2
Tiprolisant, an inverse H3-receptor agonist, has been shown to
reduce sleep cycles in mutant mice and in humans with narco- N
lepsy. Increased obesity has been demonstrated in both H1- and H
H3-receptor knockout mice; however, H3 inverse agonists decrease 5-Hydroxytryptamine (serotonin)
feeding in obese mouse models. As noted in Chapter 29, several
atypical antipsychotic drugs have significant affinity for H3 receptors
(and cause weight gain).
Because of the homology between the H3 and H4 receptors, H
some H3 ligands also have affinity for the H4 receptor. H4 blockers O CH2 N CH3
CH2 C
have potential in chronic inflammatory conditions such as H3C
asthma, in which eosinophils and mast cells play a prominent role. O
N
No selective H4 ligand is available for use in humans, but in addi- H
tion to research agents listed in Table 16–1, many H1-selective
Melatonin
blockers (eg, diphenhydramine, cetirizine, loratadine) show some (N-acetyl-5-methoxytryptamine)
affinity for this receptor. Several studies have suggested that
H4-receptor antagonists may be useful in pruritus, asthma, allergic
rhinitis, and pain conditions. FIGURE 16–2 Synthesis of serotonin and melatonin from
l-tryptophan.
■■ SEROTONIN by hydroxylation of the indole ring followed by decarboxylation

(5-HYDROXYTRYPTAMINE) of the amino acid (Figure 16–2). Hydroxylation at C5 by
tryptophan hydroxylase-1 is the rate-limiting step and can be
Before the identification of 5-hydroxytryptamine (5-HT), it was blocked by p-chlorophenylalanine (PCPA; fenclonine) and by
known that when blood is allowed to clot, a vasoconstrictor (tonic) p-chloroamphetamine. These agents have been used experimen-
substance is released from the clot into the serum. This substance tally to reduce serotonin synthesis in carcinoid syndrome but are
was called serotonin. Independent studies established the existence too toxic for general clinical use. Telotristat ethyl, an orally active
of a smooth muscle stimulant in intestinal mucosa. This was hydroxylase inhibitor, has been approved for the treatment of
called enteramine. The synthesis of 5-hydroxytryptamine in 1951 diarrhea due to carcinoid tumor.
led to the identification of serotonin and enteramine as the same After synthesis, the free amine is stored in vesicles or is rapidly
metabolite of 5-hydroxytryptophan. inactivated, usually by oxidation by monoamine oxidase (MAO).
Serotonin is an important neurotransmitter, a local hormone In the pineal gland, serotonin serves as a precursor of melatonin, a
in the gut, a component of the platelet clotting process, and is melanocyte-stimulating hormone that has complex effects in several
thought to play a role in migraine headache and several other clini- tissues. In mammals (including humans), over 90% of the serotonin
cal conditions, including carcinoid syndrome. This syndrome is an in the body is found in enterochromaffin cells in the gastrointestinal
unusual manifestation of carcinoid tumor, a neoplasm of entero- tract. In the blood, serotonin is found in platelets, which are able to
chromaffin cells. In patients whose tumor is not surgically resect- concentrate the amine by means of an active serotonin transporter
able, a serotonin antagonist may constitute a useful treatment. 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
BASIC PHARMACOLOGY OF SEROTONIN (VAT) that is blocked by reserpine. Serotonin is also found in the
raphe nuclei of the brainstem, which contain cell bodies of sero-
Chemistry & Pharmacokinetics tonergic neurons that synthesize, store, and release serotonin as a
Like histamine, serotonin is widely distributed in nature, being transmitter. Stored serotonin can be depleted by reserpine in much
found in plant and animal tissues, venoms, and stings. It is syn- the same manner as this drug depletes catecholamines from vesicles
thesized in biologic systems from the amino acid l-tryptophan in adrenergic nerves and the adrenal medulla (see Chapter 6).
Brain serotonergic neurons are involved in numerous diffuse Pharmacodynamics

functions such as mood, sleep, appetite, and temperature regula-
A. Mechanisms of Action
tion, as well as the perception of pain, the regulation of blood
pressure, and vomiting (see Chapter 21). Serotonin is clearly Serotonin exerts many actions and, like histamine, displays
involved in psychiatric depression (see Chapter 30) and also many species differences, making generalizations difficult. The
appears to be involved in conditions such as anxiety and migraine. actions of serotonin are mediated through a remarkably large
Serotonergic neurons are found in the enteric nervous system of number of cell membrane receptors. The serotonin receptors
the gastrointestinal tract and around blood vessels. In rodents (but that have been characterized thus far are listed in Table 16–3.
not in humans), serotonin is also found in mast cells. Seven families of 5-HT-receptor subtypes (those given numeric
The function of serotonin in enterochromaffin cells is not fully subscripts 1 through 7) have been identified, six involving G
understood. These cells synthesize serotonin, store the amine in a protein-coupled receptors of the usual seven-transmembrane
complex with adenosine triphosphate (ATP) and other substances serpentine type and one a ligand-gated ion channel. The latter
in granules, and release serotonin in response to mechanical and (5-HT3) receptor is a member of the nicotinic family of Na+/K+
neuronal stimuli. This serotonin interacts in a paracrine fashion channel proteins.
with several different 5-HT receptors in the gut (see Chapter 62).
Some of the released serotonin diffuses into blood vessels and is B. Tissue and Organ System Effects
taken up and stored in platelets. 1. Nervous system—Serotonin is present in a variety of sites
Serotonin is metabolized by MAO, and the intermediate in the brain. Its role as a neurotransmitter and its relation to the
product, 5-hydroxyindoleacetaldehyde, is further oxidized by actions of drugs acting in the central nervous system are discussed
aldehyde dehydrogenase to 5-hydroxyindoleacetic acid (5-HIAA). in Chapters 21 and 30. Serotonin is also a precursor of melatonin in
In humans consuming a normal diet, the excretion of 5-HIAA is the pineal gland (Figure 16–2; see Box: Melatonin Pharmacology).
a measure of serotonin synthesis. Therefore, the 24-hour excre- Repinotan, a 5-HT1A agonist currently in clinical trials, appears to
tion of 5-HIAA can be used as a diagnostic test for tumors that have some antinociceptive action at higher doses while reversing
synthesize excessive quantities of serotonin, especially carcinoid opioid-induced respiratory depression.
tumor. A few foods (eg, bananas) contain large amounts of 5-HT3 receptors in the gastrointestinal tract and in the vomit-
serotonin or its precursors and must be prohibited during such ing center of the medulla participate in the vomiting reflex (see
diagnostic tests. Chapter 62). They are particularly important in vomiting caused
TABLE 16–3 Serotonin receptor subtypes currently recognized. (See also Chapter 21.)
Receptor Postreceptor Partially Selective
Subtype Distribution Mechanism Partially Selective Agonists Antagonists
1
5-HT1A Raphe nuclei, hippocampus Gi, ↓ cAMP 8-OH-DPAT, repinotan WAY1006351
1
5-HT1B Substantia nigra, globus Gi, ↓ cAMP Sumatriptan, L694247
pallidus, basal ganglia
5-HT1D Brain Gi, ↓ cAMP Sumatriptan, eletriptan
5-HT1E Cortex, putamen Gi, ↓ cAMP
1
5-HT1F Cortex, hippocampus Gi, ↓ cAMP LY3344864
5-HT1P Enteric nervous system Go, slow EPSP 5-Hydroxyindalpine Renzapride
5-HT2A Platelets, smooth muscle, Gq, ↑ IP3 α-Methyl-5-HT, DOI1 Ketanserin
cerebral cortex
5-HT2B Stomach fundus Gq, ↑ IP3 α-Methyl-5-HT, DOI1 RS1274451
5-HT2C Choroid, hippocampus, Gq, ↑ IP3 α-Methyl-5-HT, DOI,1 lorcaserin Mesulergine
substantia nigra
5-HT3 Area postrema, sensory and Receptor is an Na+/ 2-Methyl-5-HT, m-chlorophenylbiguanide Granisetron,
enteric nerves K+ ion channel ondansetron,
others
1
5-HT4 CNS and myenteric neurons, Gs, ↑ cAMP BIMU8, renzapride, metoclopramide GR1138081
smooth muscle
5-HT5A,B Brain ↓ cAMP
5-HT6,7 Brain Gs, ↑ cAMP Clozapine (5-HT7)
1
Research 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.
Melatonin Pharmacology
Melatonin is N-acetyl-5-methoxytryptamine (Figure 16–2), a Other studies suggest that melatonin has antiapoptotic effects
simple methoxylated and N-acetylated product of serotonin in experimental models. Recent research implicates melatonin
found in the pineal gland. It is produced and released primarily receptors in depressive disorders. Insomnia associated with
at night and has long been suspected of playing a role in diurnal autism spectrum disorder may respond to melatonin.
cycles of animals and the sleep-wake behavior of humans. Melatonin is promoted commercially as a sleep aid by
Melatonin receptors have been characterized in the central the food supplement industry (see Chapter 64). There is an
nervous system and several peripheral tissues. In the brain, MT1 extensive literature supporting its use in ameliorating jet lag.
and MT2 receptors are found in membranes of neurons in the supra- It is used in oral doses of 0.5–5 mg, usually administered at the
chiasmatic nucleus of the hypothalamus, an area associated— destination bedtime. Ramelteon is a selective MT1 and MT2
from lesioning experiments—with circadian rhythm. MT1 and agonist that is approved for the medical treatment of insom-
MT2 are seven-transmembrane Gi protein-coupled receptors. nia. This drug has no addiction liability (it is not a controlled
The result of receptor binding is inhibition of adenylyl cyclase. A substance), and it appears to be distinctly more efficacious
third receptor, MT3, is an enzyme; binding to this site has a poorly than melatonin (but less efficacious than benzodiazepines) as
defined physiologic role, possibly related to intraocular pressure. a hypnotic. It is metabolized by P450 enzymes and should not
Activation of the MT1 receptor results in sleepiness, whereas the be used in individuals taking CYP1A2 inhibitors. It has a half-life
MT2 receptor may be related to the light-dark synchronization of of 1–3 hours and an active metabolite with a half-life of up to
the biologic circadian clock. Melatonin has also been implicated 5 hours. Ramelteon may increase prolactin levels. Tasimelteon
in energy metabolism and obesity, and administration of the is a newer MT1 and MT2 agonist that is approved for non-
agent reduces body weight in certain animal models. However, 24-hour sleep-wake disorder. Agomelatine, an MT1 and MT2
its role in these processes is poorly understood, and there is no agonist and a 5-HT2C antagonist, is approved in Europe for use
evidence that melatonin itself is of any value in obesity in humans. in major depressive disorder.
by chemical triggers such as cancer chemotherapy drugs. 5-HT1P the tumor. Serotonin may also cause hyperventilation as a result
and 5-HT4 receptors also play important roles in enteric nervous of the chemoreceptor reflex or stimulation of bronchial sensory
system function. nerve endings.
Like histamine, serotonin is a potent stimulant of pain and itch
sensory nerve endings and is responsible for some of the symp- 3. Cardiovascular system—Serotonin directly causes the
toms caused by insect and plant stings. In addition, serotonin is a contraction of vascular smooth muscle, mainly through 5-HT2
powerful activator of chemosensitive endings located in the coro- receptors. In humans, serotonin is a powerful vasoconstrictor except
nary vascular bed. Activation of 5-HT3 receptors on these afferent in skeletal muscle and the heart, where it dilates blood vessels.
vagal nerve endings is associated with the chemoreceptor reflex At least part of the 5-HT-induced vasodilation requires the
(also known as the Bezold-Jarisch reflex). The reflex response con- presence of vascular endothelial cells. When the endothelium
sists of marked bradycardia and hypotension, and its physiologic is damaged, coronary vessels are constricted by 5-HT. As noted
role is uncertain. The bradycardia is mediated by vagal outflow previously, serotonin can also elicit reflex bradycardia by activa-
to the heart and can be blocked by atropine. The hypotension is tion of 5-HT3 receptors on chemoreceptor nerve endings. A
a consequence of the decrease in cardiac output that results from triphasic blood pressure response is often seen following injec-
bradycardia. A variety of other agents can activate the chemore- tion of serotonin in experimental animals. Initially, there is a
ceptor reflex. These include nicotinic cholinoceptor agonists and decrease in heart rate, cardiac output, and blood pressure caused
some cardiac glycosides, eg, ouabain. by the chemoreceptor response. After this decrease, blood pressure
Although serotonergic neurons are not found below the increases as a result of vasoconstriction. The third phase is again
site of injury to the adult spinal cord, constitutive activity a decrease in blood pressure attributed to vasodilation in vessels
of 5-HT receptors may play a role following such a lesion— supplying skeletal muscle. In contrast, pulmonary and renal vessels
administration of 5-HT2 blockers appears to reduce skeletal seem very sensitive to the vasoconstrictor action of serotonin.
muscle spasm following this type of injury. Studies in knockout mice suggest that 5-HT, acting on
5-HT1A, 5-HT2, and 5-HT4 receptors, is needed for normal
2. Respiratory system—Serotonin has a small direct stimulant cardiac development in the fetus. On the other hand, chronic
effect on bronchiolar smooth muscle in normal humans, probably exposure of adults to 5-HT2B agonists is associated with val-
via 5-HT2A receptors. It also appears to facilitate acetylcholine vulopathy and adult mice lacking the 5-HT2B receptor gene are
release from bronchial vagal nerve endings. In patients with protected from cardiac hypertrophy. Preliminary studies suggest
carcinoid syndrome, episodes of bronchoconstriction occur in that 5-HT2B antagonists can prevent development of pulmonary
response to elevated levels of the amine or peptides released from hypertension in animal models.
Serotonin Syndrome and Similar Syndromes
Excess synaptic serotonin causes a serious, potentially fatal syn- animal models, many of the signs of the syndrome can be
drome that is diagnosed on the basis of a history of administration reversed by administration of 5-HT2 antagonists; however, other
of a serotonergic drug within recent weeks and physical findings. 5-HT receptors may be involved as well. Dantrolene is of no value,
It has some characteristics in common with neuroleptic malignant unlike the treatment of MH.
syndrome (NMS) and malignant hyperthermia (MH), but its patho- NMS is idiosyncratic rather than predictable and appears to
physiology and management are quite different (Table 16–4). be associated with hypersensitivity to the parkinsonism-inducing
As suggested by the drugs that precipitate it, serotonin effects of D2-blocking antipsychotics in certain individuals. MH is
syndrome occurs when overdose with a single drug, or concur- associated with a genetic defect in the RyR1 calcium channel of
rent use of several drugs, results in excess serotonergic activity in skeletal muscle sarcoplasmic reticulum that permits uncontrolled
the central nervous system. It is predictable and not idiosyncratic, calcium release from the sarcoplasmic reticulum when precipitat-
but milder forms may easily be misdiagnosed. In experimental ing drugs are given (see Chapter 27).
Serotonin also constricts veins, and venoconstriction with Serotonin has little effect on gastrointestinal secretions, and what
increased capillary filling appears to be responsible for the flush effects it has are generally inhibitory.
that is observed after serotonin administration or release from a
carcinoid tumor. Serotonin has small direct positive chronotropic 5. Skeletal muscle and the eye—5-HT2 receptors are pres-
and inotropic effects on the heart, which are probably of no clini- ent on skeletal muscle membranes, but their physiologic role is
cal significance. However, prolonged elevation of the blood level not understood. As discussed in the box, serotonin syndrome
of serotonin (which occurs in carcinoid syndrome) is associated is associated with skeletal muscle contractions and precipi-
with pathologic alterations in the endocardium (subendocardial tated when MAO inhibitors are given with serotonin agonists,
fibroplasia), which may result in valvular or electrical malfunction. especially antidepressants of the selective serotonin reuptake
Serotonin causes blood platelets to aggregate by activating 5-HT2 inhibitor class (SSRIs; see Chapter 30). Although the hyper-
receptors. This response, in contrast to aggregation induced during thermia of serotonin syndrome results from excessive muscle
normal clot formation, is not accompanied by the release of serotonin contraction, serotonin syndrome is probably caused by a
stored in the platelets. The physiologic role of this effect is unclear. central nervous system effect of these drugs (Table 16–4 and Box:
Serotonin Syndrome and Similar Syndromes).
4. Gastrointestinal tract—Serotonin is a powerful stimulant Studies in animal models of glaucoma indicate that 5-HT2A
of gastrointestinal smooth muscle, increasing tone and facili- agonists reduce intraocular pressure. This action can be blocked
tating peristalsis. This action is caused by the direct action of by ketanserin and similar 5-HT2 antagonists.
serotonin on 5-HT2 smooth muscle receptors plus a stimulating
action on ganglion cells located in the enteric nervous system (see CLINICAL PHARMACOLOGY OF
Chapter 6). 5-HT1A and 5-HT7 receptors may also be involved.
Activation of 5-HT4 receptors in the enteric nervous system causes
SEROTONIN
increased acetylcholine release and thereby mediates a motility-
enhancing or “prokinetic” effect of selective serotonin agonists Serotonin Agonists
such as cisapride. These agents are useful in several gastrointestinal Serotonin has no clinical applications as a drug. However,
disorders (see Chapter 62). Overproduction of serotonin (and other several receptor subtype-selective agonists have proved to be of
substances) in carcinoid tumor is associated with severe diarrhea. value. Buspirone, a 5-HT1A agonist, has received attention as an
TABLE 16–4 Characteristics of serotonin syndrome and other hyperthermic syndromes.

Syndrome Precipitating Drugs Clinical Presentation Therapy1
Serotonin SSRIs, second-generation antidepressants, Hypertension, hyperreflexia, tremor, Sedation (benzodiazepines),

syndrome MAOIs, linezolid, tramadol, meperidine, clonus, hyperthermia, hyperactive bowel paralysis, intubation, and ventilation;
fentanyl, ondansetron, sumatriptan, sounds, diarrhea, mydriasis, agitation, consider 5-HT2 block with cyproheptadine
MDMA, LSD, St. John’s wort, ginseng coma; onset within hours or chlorpromazine
Neuroleptic D2-blocking antipsychotics Acute severe parkinsonism; hypertension, Diphenhydramine (parenteral),
malignant hyperthermia, normal or reduced bowel cooling if temperature is very high,
syndrome sounds; onset over 1–3 days sedation with benzodiazepines
Malignant Volatile anesthetics, succinylcholine Hyperthermia, muscle rigidity, hyperten- Dantrolene, cooling
hyperthermia sion, tachycardia; onset within minutes
1
Precipitating 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.
Treatment of Obesity
It is said that much of the world is experiencing an “epidemic that bypasses the stomach and upper small intestine (but not
of obesity.” This statement is based on statistics showing that in simple restrictive banding) rapidly reverses some aspects of the
the USA and many other countries, 30–40% of the population metabolic syndrome even before significant loss of weight. Even a
is above optimal weight, and that the excess weight (especially 5–10% loss of weight is associated with a reduction in blood pres-
abdominal fat) is often associated with the metabolic syndrome sure and improved glycemic control. Gastrointestinal flora also
and increased risks of cardiovascular disease and diabetes. Since influence metabolic efficiency, and research in mice suggests that
eating behavior is an expression of endocrine, neurophysiologic, altering the microbiome can lead to weight gain or loss.
and psychological processes, prevention and treatment of obe- Until approximately 15 years ago, the most popular and
sity are challenging. There is considerable scientific and financial successful appetite suppressants were the nonselective 5-HT2
interest in developing pharmacologic therapy for the condition. agonists fenfluramine and dexfenfluramine. Combined with
Although obesity can be defined as excess adipose tissue, phentermine as Fen-Phen and Dex-Phen, they were moderately
it is currently quantitated by means of the body mass index effective. However, these 5-HT2 agonists were found to cause pulmo-
(BMI), calculated from BMI = weight (in kilograms)/height2 (in nary hypertension and cardiac valve defects and were withdrawn.
meters). Using this measure, the range of normal BMI is defined Older drugs still available in the USA and some other countries
as 18.5–24.9; overweight, 25–29.9; obese, 30–39.9; and morbidly include phenylpropanolamine, benzphetamine, amphetamine,
obese (ie, at very high risk), ≥40. (Underweight persons, ie, those methamphetamine, phentermine, diethylpropion, mazindol, and
with a BMI < 18, also have an increased [but smaller] risk of health phendimetrazine. These drugs are all amphetamine mimics
problems.) Some extremely muscular individuals may have a BMI and are central nervous system appetite suppressants; they are
higher than 25 and no excess fat; however, the BMI scale gener- generally helpful only during the first few weeks of therapy. Their
ally correlates with the degree of obesity and with risk. A second toxicity is significant and includes hypertension (with a risk of
metric, which may be an even better predictor of cardiovascular cerebral hemorrhage) and addiction liability.
risk, is the ratio of waist measurement to body height; cardiovas- Liraglutide, lorcaserin, orlistat, and phentermine are the
cular risk is lower if this ratio is less than 0.5. Experts consider drug only single-agent drugs currently approved in the USA for the treat-
therapy to be justified in patients with increased risk factors and a ment of obesity. In addition, combination agents (phentermine
BMI ≥ 27 and in those without comorbidities but with a BMI ≥ 30. plus topiramate and naltrexone plus bupropion) are available.
Although the cause of obesity can be simply stated as energy These drugs have been intensely studied, and some of their prop-
intake (dietary calories) that exceeds energy output (resting erties are listed in Table 16–5. Clinical trials and phase 4 reports
metabolism plus exercise), the actual physiology of weight con- suggest that these agents are modestly effective for the duration of
trol is extremely complex, and the pathophysiology of obesity therapy (up to 1 year) and are probably safer than the single-agent
is still poorly understood. Many hormones and neuronal mecha- amphetamine mimics. However, they do not produce more than
nisms regulate intake (appetite, satiety), processing (absorption, a 5–10% loss of weight. Mirabegron, a β3 adrenoceptor agonist
conversion to fat, glycogen, etc), and output (thermogenesis, approved for the treatment for overactive bladder (see Chapter 9),
muscle work). The fact that a large number of hormones reduce is of possible future interest because β3 agonists activate brown
appetite might appear to offer many targets for weight-reducing fat to consume more energy. Sibutramine and rimonabant were
drug therapy, but despite intensive research, no available phar- marketed for several years but were withdrawn because of increas-
macologic therapy has succeeded in maintaining a weight loss ing evidence of cardiovascular and other toxicities.
of over 10% for 1 year. Furthermore, the social and psychological Because of the low efficacy and the toxicity of the available
aspects of eating are powerful influences that are independent drugs, intensive research continues. Because of the redundancy
of or only partially dependent on the physiologic control mecha- of the physiologic mechanisms for control of body weight, it
nisms. In contrast, bariatric (weight-reducing) surgery readily seems likely that polypharmacy targeting multiple pathways will
achieves a sustained weight loss of 10–40%. Furthermore, surgery be needed to achieve success.
effective nonbenzodiazepine anxiolytic (see Chapter 22). Appe- characterized by an aura of variable duration that may involve nausea,
tite suppression appears to be associated with agonist action at vomiting, visual scotomas or even hemianopsia, and speech abnor-
5-HT2C receptors in the central nervous system, and dexfenflu- malities; the aura is followed by a severe throbbing unilateral headache
ramine, a selective 5-HT agonist, was widely used as an appetite that lasts for a few hours to 1–2 days. “Common” migraine lacks the
suppressant but was withdrawn because of cardiac valvulopathy. aura phase, but the headache is similar. After more than a century of
Lorcaserin, a 5-HT2C agonist, is approved by the FDA for use as intense study, the pathophysiology of migraine is still poorly under-
a weight-loss medication (see Box: Treatment of Obesity). stood. Although the symptom pattern and duration of prodrome
and headache vary markedly among patients, the severity of migraine
5-HT1D/1B Agonists & Migraine Headache headache justifies vigorous therapy in the great majority of cases.
The 5-HT1D/1B agonists (triptans, eg, sumatriptan) are used almost Migraine involves the trigeminal nerve distribution to intra-
exclusively for migraine headache. Migraine in its “classic” form is cranial (and possibly extracranial) arteries. These nerves release
TABLE 16–5 Antiobesity drugs and their effects.

Drug or Drug Possible Mechanism
Combination Drug Group of Action Dosage Toxicity
Orlistat GI lipase inhibitor Reduces lipid absorption 60–120 mg TID PO Decreased absorption of fat-soluble
vitamins, flatulence, fecal incontinence
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 360 mg PO TID
Phentermine Sympathomimetic Norepinephrine release in CNS 30–37.5 mg/d PO Increased BP, HR; arrhythmias, insomnia, anxiety
Phentermine/ Sympathomimetic Norepinephrine release plus 3.75–15 mg/ Insomnia, dizziness, nausea, paresthesia,
topiramate + antiseizure agent unknown mechanism 23–92 mg PO dysgeusia
BID, twice daily; BP, blood pressure; CNS, central nervous system; GI, gastrointestinal; HR, heart rate; PO, by mouth; SC, subcutaneously; TID, three times daily.
peptide neurotransmitters, especially calcitonin gene-related structure to that of the 5-HT nucleus can be seen in the structure
peptide (CGRP; see Chapter 17), an extremely powerful vaso- below. These receptor types are found in cerebral and meningeal
dilator. Substance P and neurokinin A may also be involved. vessels and mediate vasoconstriction. They are also found on neu-
Extravasation of plasma and plasma proteins into the perivascular rons and probably function as presynaptic inhibitory receptors.
space appears to be a common feature of animal migraine models
and is found in biopsy specimens from migraine patients. This CH3
CH2 CH2 N
effect probably reflects the action of the neuropeptides on the CH3
CH3 NH SO2 CH2
vessels. The mechanical stretching caused by this perivascular
edema may be the immediate cause of activation of pain nerve N
endings in the dura. The onset of headache is sometimes associated
with a marked increase in amplitude of temporal artery pulsations, Sumatriptan
and relief of pain by administration of effective therapy is some-
times accompanied by diminution of these pulsations. In population studies, all of the triptan 5-HT1 agonists
The mechanisms of action of drugs used in migraine are poorly are as effective or more effective in migraine than other acute
understood, in part because they include such a wide variety of drug treatments, eg, parenteral, oral, and rectal ergot alkaloids.
drug groups and actions. In addition to the triptans, these include However, individual drugs in this class may have different
ergot alkaloids, nonsteroidal anti-inflammatory analgesic agents,
β-adrenoceptor blockers, calcium channel blockers, tricyclic
antidepressants and SSRIs, and several antiseizure agents. Further-
100
more, some of these drug groups are effective only for prophylaxis
and not for the acute attack. Persistent Persistent Photophobia
pain nausea
Two primary hypotheses have been proposed to explain the 80
actions of these drugs. First, the triptans, the ergot alkaloids, and
Percent of patients
antidepressants may activate 5-HT1D/1B receptors on presynaptic 60

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 40
5-HT agonists (the triptans and ergot) may prevent vasodilation
and stretching of the pain endings. It is possible that both mecha- 20
nisms contribute in the case of some drugs.
Sumatriptan and its congeners are currently first-line therapy
0
for acute severe migraine attacks in most patients (Figure 16–3). P S P S P S
However, they should not be used in patients at risk for coronary Treatment (P = placebo, S = sumatriptan)
artery disease. Anti-inflammatory analgesics such as aspirin and
ibuprofen are often helpful in controlling the pain of migraine. FIGURE 16–3 Effects of sumatriptan (734 patients) or placebo
Rarely, parenteral opioids may be needed in refractory cases. (370 patients) on symptoms of acute migraine headache 60 minutes
For patients with very severe nausea and vomiting, parenteral after injection of 6 mg subcutaneously. All differences between
metoclopramide may be helpful. placebo and sumatriptan were statistically significant. (Data from
Sumatriptan and the other triptans are selective agonists 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.

Maximum Dose
Drug Routes Time to Onset (h) Single Dose (mg) per Day (mg) Half-Life (h)
Almotriptan Oral 2.6 6.25–12.5 25 3.3

Eletriptan Oral 2 20–40 80 4
Frovatriptan Oral 3 2.5 7.5 27
Naratriptan Oral 2 1–2.5 5 5.5
Rizatriptan Oral 1–2.5 5–10 30 2
Sumatriptan Oral, nasal, subcutaneous, 1.5 (0.2 for 25–100 (PO), 20 nasal, 200 2
rectal subcutaneous) 6 subcutaneous, 25 rectal
Zolmitriptan Oral, nasal 1.5–3 2.5–5 10 2.8
efficacies in individual patients. The pharmacokinetics and potencies Cisapride, a 5-HT4 agonist, was used in the treatment of
of the triptans differ significantly and are set forth in Table 16–6. gastroesophageal reflux and motility disorders. Because of toxicity,
Most adverse effects are mild and include altered sensations it is now available only for compassionate use in the USA. Tegas-
(tingling, warmth, etc), dizziness, muscle weakness, neck pain, erod, a 5-HT4 partial agonist, is used for irritable bowel syndrome
and for parenteral sumatriptan, injection site reactions. Chest with constipation (see Chapter 62).
discomfort occurs in 1–5% of patients, and chest pain has been Compounds such as fluoxetine and other SSRIs, which
reported, probably because of the ability of these drugs to cause modulate serotonergic transmission by blocking reuptake of the
coronary vasospasm. They are therefore contraindicated in patients transmitter, are among the most widely prescribed drugs for the
with coronary artery disease and in patients with angina. Another management of depression and similar disorders. These drugs are
disadvantage is the fact that their duration of effect (especially discussed in Chapter 30.
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 SEROTONIN ANTAGONISTS
migraine attack, but their adverse effects limit the maximum safe
The actions of serotonin, like those of histamine, can be antago-
daily dosage. Naratriptan and eletriptan are contraindicated in
patients with severe hepatic or renal impairment or peripheral vas- nized in several ways. Such antagonism is clearly desirable in those
cular syndromes; frovatriptan in patients with peripheral vascular rare patients who have carcinoid tumor and may also be valuable
disease; and zolmitriptan in patients with Wolff-Parkinson-White in certain other conditions.
syndrome. The brand name triptans are extremely expensive; thus Serotonin synthesis can be inhibited by p-chlorophenylalanine
generic sumatriptan should be used whenever possible. and p-chloroamphetamine. However, these agents are too toxic
Propranolol, amitriptyline, and some calcium channel block- for general use. Storage of serotonin can be inhibited by the use of
ers have been found to be effective for the prophylaxis of migraine reserpine, but the sympatholytic effects of this drug (see Chapter 11)
in some patients. They are of no value in the treatment of acute and the high levels of circulating serotonin that result from release
migraine. The anticonvulsants valproic acid and topiramate (see prevent its use in carcinoid. Therefore, receptor blockade is the
Chapter 24) have also been found to have some prophylactic effi- major therapeutic approach to conditions of serotonin excess.
cacy 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 SEROTONIN-RECEPTOR
appears to have modest efficacy as prophylaxis against migraine. ANTAGONISTS
A wide variety of drugs with actions at other receptors (eg,
Other Serotonin Agonists in Clinical Use α adrenoceptors, H1-histamine receptors) also have serotonin
Flibanserin, a 5-HT1a agonist and 5-HT2A antagonist, is approved receptor-blocking effects. Phenoxybenzamine (see Chapter 10)
for treatment of hypoactive sexual desire disorder in women. Due has a long-lasting blocking action at 5-HT2 receptors. In addition,
to inadequate evidence of efficacy, it was refused approval in the ergot alkaloids discussed in the last portion of this chapter are
2010 and 2013. The clinical trials that led to its approval in 2015 partial agonists at serotonin receptors.
showed a very small but significant increase in satisfactory sexual Cyproheptadine resembles the phenothiazine antihistaminic
desire and activities over several weeks of daily oral administra- agents in chemical structure and has potent H1-receptor-blocking
tion. Consumption of alcohol is contraindicated due to increased as well as 5-HT2-blocking actions. The actions of cyproheptadine
risk of severe hypotension. Other adverse effects include syncope, are predictable from its H1 histamine and 5-HT receptor affini-
nausea, fatigue, dizziness, and somnolence. ties. It prevents the smooth muscle effects of both amines but has
no effect on the gastric secretion stimulated by histamine. It also acetylcholine, tyramine, and other biologically active products in
has significant antimuscarinic effects and causes sedation. addition to a score or more of unique ergot alkaloids. These alka-
The major clinical applications of cyproheptadine are in the loids affect α adrenoceptors, dopamine receptors, 5-HT receptors,
treatment of the smooth muscle manifestations of carcinoid and perhaps other receptor types. Similar alkaloids are produced
tumor and in cold-induced urticaria. The usual dosage in adults by fungi parasitic to a number of other grass-like plants.
is 12–16 mg/d orally in three or four divided doses. It is of some The accidental ingestion of ergot alkaloids in contaminated
value in serotonin syndrome, but because it is available only in grain can be traced back more than 2000 years from descriptions
tablet form, cyproheptadine must be crushed and administered by of epidemics of ergot poisoning (ergotism). The most dramatic
stomach tube in unconscious patients. The drug also appears to effects of poisoning are dementia with florid hallucinations;
reduce muscle spasms following spinal cord injury, in which con- prolonged vasospasm, which may result in gangrene; and stimu-
stitutive activity of 5-HT2C receptors is associated with increases lation of uterine smooth muscle, which in pregnancy may result
in Ca2+ currents leading to spasms. Anecdotal evidence suggests in abortion. In medieval times, ergot poisoning was called
some efficacy as an appetite stimulant in cancer patients, but St. Anthony’s fire after the saint whose help was sought in
controlled trials have yielded mixed results. relieving the burning pain of vasospastic ischemia. Identifiable
Ketanserin blocks 5-HT2 receptors on smooth muscle and epidemics have occurred sporadically up to modern times (see
other tissues and has little or no reported antagonist activity at Box: Ergot Poisoning: Not Just an Ancient Disease) and mandate
other 5-HT or H1 receptors. However, this drug potently blocks continuous surveillance of all grains used for food. Poisoning of
vascular α1 adrenoceptors. The drug blocks 5-HT2 receptors on grazing animals is common in many areas because the fungus
platelets and antagonizes platelet aggregation promoted by may grow on pasture grasses.
serotonin. The mechanism involved in ketanserin’s hypotensive In addition to the effects noted above, the ergot alkaloids
action probably involves α1 adrenoceptor blockade more than produce a variety of other central nervous system and peripheral
5-HT2 receptor blockade. Ketanserin is available in Europe for effects. Detailed structure-activity analysis and appropriate semi-
the treatment of hypertension and vasospastic conditions but synthetic modifications have yielded a large number of agents of
has not been approved in the USA. Ritanserin, another 5-HT2 experimental and clinical interest.
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. BASIC PHARMACOLOGY OF ERGOT
Ondansetron is the prototypical 5-HT3 antagonist. This drug
and its analogs are very important in the prevention of nausea and
ALKALOIDS
vomiting associated with surgery and cancer chemotherapy. They
are discussed in Chapter 62. Chemistry & Pharmacokinetics
Considering the diverse effects attributed to serotonin and the Two major families of compounds that incorporate the tetracyclic
heterogeneous nature of 5-HT receptors, other selective 5-HT ergoline nucleus may be identified; the amine alkaloids and the
antagonists may prove to be clinically useful. peptide alkaloids (Table 16–7). Drugs of therapeutic and toxico-
logic importance are found in both groups.
The ergot alkaloids are variably absorbed from the gastro-
■■ THE ERGOT ALKALOIDS intestinal tract. The oral dose of ergotamine is about 10 times
larger than the intramuscular dose, but the speed of absorption
Ergot alkaloids are produced by Claviceps purpurea, a fungus that and peak blood levels after oral administration can be improved
infects grasses and grains—especially rye—under damp growing by administration with caffeine (see below). The amine alkaloids
or storage conditions. This fungus synthesizes histamine, are also absorbed from the rectum and the buccal cavity and after
Ergot Poisoning: Not Just an Ancient Disease
As noted in the text, epidemics of ergotism, or poisoning by ergotism occurred in the small French village of Pont-Saint-Esprit
ergot-contaminated grain, are known to have occurred sporadi- in 1951. It was vividly described in the British Medical Journal in
cally in ancient times and through the Middle Ages. It is easy to 1951 (Gabbai et al, 1951) and in a later book-length narrative
imagine the social chaos that might result if fiery pain, gangrene, account (Fuller, 1968). Several hundred individuals suffered symp-
hallucinations, convulsions, and abortions occurred simultane- toms of hallucinations, convulsions, and ischemia—and several
ously throughout a community in which all or most of the people died—after eating bread made from contaminated flour. Similar
believed in witchcraft, demonic possession, and the visitation events have occurred even more recently when poverty, famine,
of supernatural punishments upon humans for their misdeeds. or incompetence resulted in the consumption of contaminated
Fortunately, such beliefs are uncommon today. However, ergot- grain. Ergot toxicity caused by excessive self-medication with
ism has not disappeared. A most convincing demonstration of pharmaceutical ergot preparations is still occasionally reported.
TABLE 16–7 Major ergoline derivatives (ergot alkaloids).
Amine alkaloids Peptide alkaloids

H R8
8 O O
9 7 R2′
D N
6 H C NH 2′
5 N
12 10 CH3 N 5′
13 11
A C 9 O O
14 16 4 H R 5′
15 N
B 3 10 CH3
1 2
R1 N
1 2
HN R2
R1 R8 R2 R 2′ R 5′
6-Methylergoline H H
Ergotamine1 H CH3 CH2
Lysergic acid H COOH
Lysergic acid H O
diethylamide α-Ergocryptine H CH(CH3)2 CH2 CH(CH3)2
(LSD) C N(CH2 CH3)2
Ergonovine H O CH2OH Bromocriptine Br CH(CH3)2 CH2 CH(CH3)2

(ergometrine)
C NHCHCH3
1
Dihydroergotamine lacks the double bond between carbons 9 and 10.
administration by aerosol inhaler. Absorption after intramuscular catecholamines (phenylethylamine, left panel) and 5-HT (indole-
injection is slow but usually reliable. Semisynthetic analogs such thylamine, right panel) can be discerned in the ergoline nucleus.
as bromocriptine and cabergoline are well absorbed from the Their effects include agonist, partial agonist, and antagonist
gastrointestinal tract. actions at α adrenoceptors and serotonin receptors (especially
The ergot alkaloids are extensively metabolized in the body. 5-HT1A and 5-HT1D; less for 5-HT2 and 5-HT3); and agonist
The primary metabolites are hydroxylated in the A ring, and or partial agonist actions at central nervous system dopamine
peptide alkaloids are also modified in the peptide moiety. 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
Pharmacodynamics a powerful stimulant effect on the uterus that seems to be most
A. Mechanism of Action closely associated with agonist or partial agonist effects at 5-HT2
The ergot alkaloids act on several types of receptors. As receptors. Structural variations increase the selectivity of certain
shown by the color outlines in Table 16–7, the nuclei of both members of the family for specific receptor types.
TABLE 16–8 Effects of ergot alkaloids at several receptors.1

Serotonin Receptor Uterine Smooth
Ergot Alkaloid α Adrenoceptor Dopamine Receptor (5-HT2) Muscle Stimulation
Bromocriptine − +++ − 0
Ergonovine ++ − (PA) +++ ++
Ergotamine − − (PA) 0 +(PA) +++
Lysergic acid diethylamide (LSD) 0 +++ − − (++ in CNS) +
Methysergide +/0 +/0 − − − (PA) +/0
1
Agonist 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 action (Table 16–7). Because ergotamine dissociates very slowly
1. Central nervous system—As indicated by traditional from the α receptor, it produces very long-lasting agonist and
descriptions of ergotism, certain of the naturally occurring alka- antagonist effects at this receptor. There is little or no effect at β
loids are powerful hallucinogens. Lysergic acid diethylamide adrenoceptors.
(LSD; “acid”) is a synthetic ergot compound that clearly dem- Although much of the vasoconstriction elicited by ergot
onstrates this action. The drug has been used in the laboratory alkaloids can be ascribed to partial agonist effects at α adreno-
as a potent peripheral 5-HT2 antagonist, but good evidence sug- ceptors, some may be the result of effects at 5-HT receptors.
gests that its behavioral effects are mediated by agonist effects at Ergotamine, ergonovine, and methysergide all have partial agonist
prejunctional or postjunctional 5-HT2 receptors in the central effects at 5-HT2 vascular receptors. The remarkably selective
nervous system. In spite of extensive research, no clinical value has antimigraine action of the ergot derivatives was originally thought
been discovered for LSD’s dramatic central nervous system effects. to be related to their actions on vascular serotonin receptors. Cur-
Abuse of this drug has waxed and waned but is still widespread. It rent hypotheses, however, emphasize their action on prejunctional
is discussed in Chapter 32. neuronal 5-HT receptors.
Dopamine receptors in the central nervous system play After overdosage with ergotamine and similar agents, vasospasm
important roles in extrapyramidal motor control and the regu- is severe and prolonged (see Toxicity, below). This vasospasm is
lation of pituitary prolactin release. The actions of the peptide not easily reversed by α antagonists, serotonin antagonists, or
ergoline bromocriptine on the extrapyramidal system are dis- combinations of both.
cussed in Chapter 28. Of all the currently available ergot Ergotamine is typical of the ergot alkaloids that have a strong
derivatives, bromocriptine, cabergoline, and pergolide have the vasoconstrictor action. The hydrogenation of ergot alkaloids at
highest selectivity for the pituitary dopamine receptors. These the 9 and 10 positions (Table 16–6) yields dihydro derivatives
drugs directly suppress prolactin secretion from pituitary cells that have reduced serotonin partial agonist and vasoconstrictor
by activating regulatory dopamine receptors (see Chapter 37). effects and increased selective α-receptor-blocking actions.
They compete for binding to these sites with dopamine itself and
3. Uterine smooth muscle—The stimulant action of ergot
with other dopamine agonists such as apomorphine. They bind alkaloids on the uterus, as on vascular smooth muscle, appears
with high affinity and dissociate slowly. to combine α agonist, serotonin agonist, and other effects.
Furthermore, the sensitivity of the uterus to the stimulant
2. Vascular smooth muscle—The actions of ergot alkaloids effects of ergot increases dramatically during pregnancy, perhaps
on vascular smooth muscle are drug-, species-, and vessel- because of increasing dominance of α1 receptors of the uterus
dependent, so few generalizations are possible. In humans, ergota- as pregnancy progresses. As a result, the uterus at term is more
mine and similar compounds constrict most vessels in nanomolar sensitive to ergot than earlier in pregnancy and far more sensi-
concentrations (Figure 16–4). The vasospasm is prolonged. This tive than the nonpregnant organ.
response is partially blocked by conventional α-blocking agents. In very small doses, ergot preparations can evoke rhythmic
However, ergotamine’s effect is also associated with “epinephrine contraction and relaxation of the uterus. At higher concentra-
reversal” (see Chapter 10) and with blockade of the response to tions, these drugs induce powerful and prolonged contracture.
other α agonists. This dual effect reflects the drug’s partial agonist Ergonovine is more selective than other ergot alkaloids in affecting
120
Percent of maximum 5-HT contraction
NE
100
5-HT
80
60
ERG MT
40
DHE
20
MS
0
−10 −9 −8 −7 −6 −5 −4
Concentration (log M)
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, dihydroergota-
mine; 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 even been associated with regression of the tumor in some
ergot drugs although oxytocin, the peptide hormone, is preferred cases. The usual dosage of bromocriptine is 2.5 mg two or
in most cases. three times daily. Cabergoline is similar but more potent.
Bromocriptine has also been used in the same dosage to sup-
4. Other smooth muscle organs—In most patients, the ergot press physiologic lactation. However, serious postpartum car-
alkaloids have little or no effect on bronchiolar or urinary smooth diovascular toxicity has been reported in association with the
muscle. The gastrointestinal tract, on the other hand, is quite latter use of bromocriptine or pergolide, and this application
sensitive. In some patients, nausea, vomiting, and diarrhea may be is discouraged (see Chapter 37).
induced even by low doses. The effect is consistent with action on
the central nervous system emetic center and on gastrointestinal C. Postpartum Hemorrhage
serotonin receptors. 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
CLINICAL PHARMACOLOGY OF derivatives should be used only for control of postpartum uterine
ERGOT ALKALOIDS bleeding and should never be given before delivery. Oxytocin is
the preferred agent for control of postpartum hemorrhage, but
Clinical Uses if this peptide agent is ineffective, ergonovine maleate, 0.2 mg
given intramuscularly, can be tried. It is usually effective within
Despite their significant toxicities, ergot alkaloids are still widely
1–5 minutes and is less toxic than other ergot derivatives for this
used in patients with migraine headache or pituitary dysfunction.
application. It is given at the time of delivery of the placenta or
They are used only occasionally in the postpartum patient.
immediately afterward if bleeding is significant.
A. Migraine
D. Diagnosis of Variant Angina
Ergot derivatives are highly specific for migraine pain; they are
Ergonovine given intravenously has been used to produce
not analgesic for any other condition. Although the triptan drugs
prompt vasoconstriction during coronary angiography to diag-
discussed above are preferred by most clinicians and patients, tra-
nose variant angina if reactive segments of the coronary arteries
ditional therapy with ergotamine can also be effective when given
are present. In Europe, methylergometrine has been used for
during the prodrome of an attack; it becomes progressively less
this purpose.
effective if delayed. Ergotamine tartrate is available for oral, sub-
lingual, rectal suppository, and inhaler use. It is often combined
E. Senile Cerebral Insufficiency
with caffeine (100 mg caffeine for each 1 mg ergotamine tartrate)
to facilitate absorption of the ergot alkaloid. Dihydroergotoxine, a mixture of dihydro-α-ergocryptine and
The vasoconstriction induced by ergotamine is long-lasting three similar dihydrogenated peptide ergot alkaloids (ergoloid
and cumulative when the drug is taken repeatedly, as in a severe mesylates), has been promoted for many years for the relief
migraine attack. Therefore, patients must be carefully informed of signs of senility and, more recently, for the treatment of
that no more than 6 mg of the oral preparation may be taken for Alzheimer’s dementia. There is no useful evidence that this drug
each attack and no more than 10 mg per week. For very severe has significant benefit.
attacks, ergotamine tartrate, 0.25–0.5 mg, may be given intrave-
nously or intramuscularly. Dihydroergotamine, 0.5–1 mg intrave- Toxicity & Contraindications
nously, is favored by some clinicians for treatment of intractable The most common toxic effects of the ergot derivatives are
migraine. Intranasal dihydroergotamine may also be effective. gastrointestinal disturbances, including diarrhea, nausea, and
Methysergide, which was used for migraine prophylaxis in the vomiting. Activation of the medullary vomiting center and of the
past, was withdrawn because of toxicity, see below. gastrointestinal serotonin receptors is involved. Since migraine
attacks are often associated with these symptoms before therapy
B. Hyperprolactinemia is begun, these adverse effects are rarely contraindications to the
Increased serum levels of the anterior pituitary hormone prolactin use of ergot.
are associated with secreting tumors of the gland and also with A more dangerous toxic effect—usually associated with
the use of centrally acting dopamine antagonists, especially the overdosage—of agents like ergotamine and ergonovine is
D2-blocking antipsychotic drugs. Because of negative feedback prolonged vasospasm. This sign of vascular smooth muscle
effects, hyperprolactinemia is associated with amenorrhea and stimulation may result in gangrene and may require amputation.
infertility in women as well as galactorrhea in both sexes. Rarely, Bowel infarction has also been reported and may require resection.
the prolactin surge that occurs around the end-of-term pregnancy Vasospasm caused by ergot is refractory to most vasodilators, but
may be associated with heart failure; cabergoline has been used to infusion of large doses of nitroprusside or nitroglycerin has been
treat this cardiac condition successfully. successful in some cases.
Bromocriptine is extremely effective in reducing the high Chronic therapy with methysergide was associated with con-
levels of prolactin that result from pituitary tumors and has nective tissue proliferation in the retroperitoneal space, the pleural
cavity, and the endocardial tissue of the heart. These changes was sometimes used as a substitute for LSD by members of the
occurred insidiously over months and presented as hydronephro- so-called drug culture.
sis (from obstruction of the ureters) or a cardiac murmur (from Contraindications to the use of ergot derivatives consist of the
distortion of the valves of the heart). In some cases, valve damage obstructive vascular diseases, especially symptomatic coronary
required surgical replacement. As a result, this drug was with- artery disease, and collagen diseases.
drawn from the US market. Similar fibrotic change has resulted There is no evidence that ordinary use of ergotamine for
from the chronic use of non-ergot 5-HT agonists promoted in the migraine is hazardous in pregnancy. However, most clinicians
past for weight loss (fenfluramine, dexfenfluramine). counsel restraint in the use of the ergot derivatives by preg-
Other toxic effects of the ergot alkaloids include drowsi- nant patients. Use to deliberately cause abortion is contrain-
ness and, in the case of methysergide, occasional instances of dicated because the high doses required often cause dangerous
central stimulation and hallucinations. In fact, methysergide vasoconstriction.
SUMMARY Drugs with Actions on Histamine and Serotonin Receptors; Ergot

Alkaloids
Mechanism Clinical Pharmacokinetics, Toxicities,
Subclass, Drug of Action Effects Applications Interactions
H1 ANTIHISTAMINES
First generation:
• Diphenhydramine Competitive Reduces or prevents histamine IgE immediate Oral and parenteral • duration 4–6 h • Toxicity:
antagonism/inverse effects on smooth muscle, allergies; especially Sedation when used in hay fever, muscarinic
agonism at H1 immune cells • also blocks hay fever, urticaria blockade symptoms, orthostatic hypotension
receptors muscarinic and α adrenoceptors • often used as a • Interactions: Additive sedation with other
• highly sedative sedative, antiemetic, sedatives, including alcohol • some inhibition of
and anti-motion CYP2D6, may prolong action of some β blockers
sickness drug
Second generation:
• Cetirizine Competitive Reduces or prevents histamine IgE immediate Oral • duration 12–24 h • Toxicity: Sedation and
antagonism/inverse effects on smooth muscle, allergies; especially arrhythmias in overdose • Interactions: Minimal
agonism at H1 immune cells hay fever, urticaria
receptors
• 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 (see Chapter 62)
SEROTONIN AGONISTS
5-HT1B/1D:
• Sumatriptan Partial agonist at Effects not fully understood Migraine and cluster Oral, nasal, parenteral • duration 2 h • Toxicity:
5-HT1B/1D receptors • may reduce release of headache Paresthesias, dizziness, coronary
calcitonin gene-related peptide vasoconstriction • Interactions: Additive with
and perivascular edema in other vasoconstrictors
cerebral circulation
• 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
5-HT2C:
• Lorcaserin Agonist at 5-HT2C Appears to reduce appetite Obesity Oral • duration 11 h • Toxicity: Dizziness,
receptors headache, constipation
5-HT4:
• Tegaserod (see Chapter 62)
(continued)
Mechanism Clinical Pharmacokinetics, Toxicities,

Subclass, Drug of Action Effects Applications Interactions
SEROTONIN BLOCKERS
5-HT2:
• Ketanserin (not Competitive Prevents vasoconstriction and Hypertension Oral • duration 12–24 h • Toxicity: Hypotension
available in USA) blockade at 5-HT2 bronchospasm of carcinoid • carcinoid syndrome
receptors syndrome associated with
carcinoid tumor
5-HT3:
• Ondansetron, others (see Chapter 62)
ERGOT ALKALOIDS
Vasoselective:
• Ergotamine Mixed partial agonist Causes marked smooth muscle Migraine and cluster Oral, parenteral • duration 12–24 h • Toxicity:
effects at 5-HT2 and contraction but blocks headache Prolonged vasospasm causing angina,
α adrenoceptors α-agonist vasoconstriction gangrene; uterine spasm
Uteroselective:
• Ergonovine Mixed partial agonist Same as ergotamine • some Postpartum bleeding Oral, parenteral (methylergonovine) • duration
effects at 5-HT2 and selectivity for uterine smooth • migraine headache 2–4 h • Toxicity: Same as ergotamine
α adrenoceptors muscle
CNS selective:
• Lysergic acid Central nervous Hallucinations None • widely Oral • duration several hours • Toxicity:
diethylamide system 5-HT2 and • psychotomimetic abused Prolonged psychotic state, flashbacks
dopamine agonist
• 5-HT2 antagonist in
periphery
• Bromocriptine, pergolide: Ergot derivatives used in Parkinson’s disease (see Chapter 28) and prolactinoma (see Chapter 37). Pergolide used in equine
Cushing’s disease
P R E P A R A T I O N S A V A I L A B L E
GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

ANTIHISTAMINES (H 1 BLOCKERS) * Fexofenadine Generic, Allegra
Azelastine Generic, Astelin (nasal), Optivar
Hydroxyzine Generic, Vistaril
(ophthalmic)
Ketotifen Generic, Zaditor
Brompheniramine Brovex, Dimetapp, others
Levocabastine Livostin
Buclizine Bucladin-S Softabs
Levocetirizine Generic, Xyzal
Carbinoxamine Generic, Histex
Loratadine Generic, Claritin
Cetirizine Generic, Zyrtec
Chlorpheniramine Generic, Chlor-Trimeton Meclizine Generic, Antivert, Bonine
Clemastine Generic, Tavist Olopatadine Patanol, Pataday
Cyclizine Generic, Marezine Phenindamine Nolahist
Cyproheptadine Generic, Periactin Promethazine Generic, Phenergan
Desloratadine Generic, Clarinex Triprolidine Generic, Zymine, Tripohist
Dimenhydrinate †
Generic, Dramamine H 2 BLOCKERS
Diphenhydramine Generic, Benadryl See Chapter 62.
Doxylamine Diclegis (combination with 5-HT AGONISTS

pyridoxine), Unisom Sleep Tabs Almotriptan Axert
Epinastine Generic, Elestat Eletriptan Relpax
(continued)
GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

Flibanserin Addyi Ergonovine Generic, Ergotrate
Frovatriptan Frova Ergotamine mixtures Generic, Cafergot
Naratriptan Generic, Amerge (include caffeine)
Rizatriptan Generic, Maxalt, Maxalt-MLT Ergotamine tartra Generic, Ergomar
Sumatriptan Generic, Imitrex Methylergonovine Generic, Methergine
Zolmitriptan Generic, Zomig ANTIOBESITY DRUGS
5-HT ANTAGONISTS Liraglutide Saxenda, Victoza

See Chapter 62. Lorcaserin Belviq
MELATONIN RECEPTOR AGONISTS Naltrexone/bupropion Contrave
Ramelteon Rozarem Orlistat Alli, Xenical
Tasimelteon Hetlioz Phentermine Generic, Adipex-P,
ERGOT ALKALOIDS Lomaira
Dihydroergotamine Generic, Migranal, D.H.E. 45 Phentermine/topiramate Qsymia
*Several other antihistamines are available only in combination products with, for example, phenylephrine.
†
Dimenhydrinate is the chlorotheophylline salt of diphenhydramine.
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Keet C: Recognition and management of food induced anaphylaxis. Pediatr Clin Porvasnik SL et al: PRX-08066, a novel 5-hydroxytryptamine receptor 2B
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McParlin C et al: Treatments of hyperemesis gravidarum and nausea and vomiting 334:364.
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Raymond JR et al: Multiplicity of mechanisms of serotonin receptor signal trans-
Niebyl JR: Nausea and vomiting in pregnancy. N Engl J Med 2010;363:1544. duction. Pharmacol Ther 2001;92:179.
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C ASE STUDY ANSWER
These patients demonstrate typical symptoms and signs termed scombroid poisoning (Scombridae family of fish is
caused by histamine. Fortunately, neither patient in this most commonly associated with this toxicity). Treatment
episode of food poisoning had significant laryngeal edema with maximal doses of histamine blockers, especially H1
or bronchospasm. Certain types of fish, if improperly blockers, is usually sufficient to control the symptoms.
preserved, contain large quantities of histamine, due to Because this is not an allergic reaction, administration of
the conversion—by bacteria contaminating the muscle epinephrine is not necessary unless hypotension or airway
tissue—of histidine to histamine. If consumed in suf- obstruction is severe. (See Edlow JA: The Deadly Dinner
ficient amount, enough histamine can be absorbed to Party: And Other Medical Detective Stories. Yale University
cause the clinical picture described. This syndrome is Press, 2009.)

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SECTION IV DRUGS WITH IMPORTANT ACTIONS ON

TABLE 16–1 Histamine receptor subtypes.

Other Histamine Agonists ■■ HISTAMINE RECEPTOR

General structure Ethers or ethanolamine derivative

Alkylamine derivative Piperidine derivative

CH2 CH2 CH2 CH C COOH

2. Antinausea and antiemetic actions—Several first-generation 6. Serotonin-blocking actions—Strong blocking effects at

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

8. Other actions—Certain H1 antagonists, eg, cetirizine, inhibit

Angioedema may be precipitated by histamine release but Toxicity

■■ SEROTONIN by hydroxylation of the indole ring followed by decarboxylation

Brain serotonergic neurons are involved in numerous diffuse Pharmacodynamics

Serotonin Syndrome and Similar Syndromes

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

Serotonin SSRIs, second-generation antidepressants, Hypertension, hyperreflexia, tremor, Sedation (benzodiazepines),

TABLE 16–5 Antiobesity drugs and their effects.

antidepressants may activate 5-HT1D/1B receptors on presynaptic 60

TABLE 16–6 Pharmacokinetics of triptans.

Almotriptan Oral 2.6 6.25–12.5 25 3.3

Ergot Poisoning: Not Just an Ancient Disease

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

Amine alkaloids Peptide alkaloids

Ergonovine H O CH2OH Bromocriptine Br CH(CH3)2 CH2 CH(CH3)2

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

SUMMARY Drugs with Actions on Histamine and Serotonin Receptors; Ergot

Mechanism Clinical Pharmacokinetics, Toxicities,

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

Clemastine Generic, Tavist Olopatadine Patanol, Pataday

Cyclizine Generic, Marezine Phenindamine Nolahist

Cyproheptadine Generic, Periactin Promethazine Generic, Phenergan

Desloratadine Generic, Clarinex Triprolidine Generic, Zymine, Tripohist

Diphenhydramine Generic, Benadryl See Chapter 62.

Doxylamine Diclegis (combination with 5-HT AGONISTS

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

Rizatriptan Generic, Maxalt, Maxalt-MLT Ergotamine tartra Generic, Ergomar

Sumatriptan Generic, Imitrex Methylergonovine Generic, Methergine

Zolmitriptan Generic, Zomig ANTIOBESITY DRUGS

5-HT ANTAGONISTS Liraglutide Saxenda, Victoza

REFERENCES Barrenetxe J, Delagrange P, Martinez JA: Physiologic and metabolic functions of

C ASE STUDY ANSWER

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